Enhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats.

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is a serious neurologic complication in patients with liver cirrhosis. Very little is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE. METHODS: A 4-week bile duct ligation model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated by using archived GSE41919. The motor function of rats was assessed by the rotarod test. Adeno-associated virus 8-vascular endothelial growth factor C (AAV8-VEGF-C) was injected into the cisterna magna of HE rats 1 day after surgery to induce meningeal lymphangiogenesis. RESULTS: Cirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (P < .001) as well as increased neuroinflammation, as indicated by significant increases in interleukin 1ß, interferon γ, tumor necrosis factor α, and ionized calcium binding adaptor molecule 1 (Iba1) expression levels in at least 1 of the 3 regions of the cortex. Motor function was also impaired in rats with HE (P < .05). Human brains of patients with cirrhosis with HE also exhibited up-regulation of proinflammatory genes (NFKB1, IbA1, TNF-α, and IL1ß) (n = 6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (P = .035) and tracer dye uptake in the anterior and middle regions of the cortex (P = .006 and .003, respectively), their corresponding meninges (P = .086 and .006, respectively), and the draining lymph nodes (P = .02). Furthermore, AAV8-VEGF-C decreased microglia activation (P < .001) and neuroinflammation and ameliorated motor dysfunction (P = .024). CONCLUSIONS: Promoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.

Calprotectin as Diagnostic Marker for Hepatic Encephalopathy and Spontaneous Bacterial Peritonitis in Cirrhosis.

BACKGROUND: Calprotectin is a well-established marker for intestinal inflammation, mainly in inflammatory bowel disease, and represents one of the most studied biomarkers in stool samples. METHODS: Apart from its important diagnostic role in inflammatory bowel disease, there are few studies showing that calprotectin can also be used as a diagnostic tool in patients suffering from hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP) in cirrhosis. RESULTS: Since calprotectin concentration in the human stool or in ascites is elevated at an early stage of inflammation, it might serve as an early screening tool for patients suffering from cirrhosis who are at risk to develop these conditions. As detection and monitoring of HE and SBP may be unclear and resource-intensive, identification of valid new markers of disease activity is necessary. In this review, we summarize the current knowledge of calprotectin as a diagnostic biomarker in cirrhosis, indicating that it is a highly promising diagnostic surrogate marker to screen for the presence of HE and SBP. CONCLUSIONS: To screen cirrhotic patients for SBP, calprotectin should be assessed in ascitic fluid while it should be measured in feces when screening for HE. However, the value of calprotectin in managing individual patients must be considered in the specific clinical context.

Selective improvement by rifaximin of changes in the immunophenotype in patients who improve minimal hepatic encephalopathy.

BACKGROUND: Minimal hepatic encephalopathy (MHE) in cirrhotic patients is associated with specific changes in parameters of the immune system reflecting a more pro-inflammatory environment than in patients without MHE. The aims of this work were to assess the effects of rifaximin treatment of cirrhotic patients with MHE on: (1) MHE; (2) intermediate (CD14++CD16+) pro-inflammatory monocytes; (3) expression of early activation marker CD69 in T lymphocytes; (4) autoreactive CD4+CD28- T lymphocytes; (5) differentiation of CD4+ T lymphocytes to Th follicular and Th22; (6) serum IgG levels; and (7) levels of some pro-inflammatory cytokines. METHODS: These parameters were measured by immunophenotyping and cytokine profile analysis in 30 controls without liver disease, 30 cirrhotic patients without MHE and 22 patients with MHE. Patients with MHE were treated with rifaximin and the same parameters were measured at 3 and 6 months of treatment. We assessed if changes in these parameters are different in patients who improve MHE (responders) and those who remain in MHE (non-responders). RESULTS: Rifaximin improved MHE in 59% of patients with MHE. In these responder patients rifaximin normalized all alterations in the immune system measured while in non-responders it normalizes only IL-6, CCL20, and differentiation of T lymphocytes to Th22. Non-responder patients do not show increased expression of CD69 before treatment. CONCLUSIONS: Rifaximin normalizes changes in the immune system in patients who improve MHE but not in non-responders. Some alterations before treatment are different in responders and non-responders. Understanding these differences may identify predictors of the response of MHE to rifaximin.

L-ornithine L-aspartate in bouts of overt hepatic encephalopathy.

High-quality data on the efficacy of L-ornithine L-aspartate (LOLA) in patients with cirrhosis and bouts of overt hepatic encephalopathy (OHE) are missing. We evaluated the efficacy of intravenous LOLA in the reversal of bouts of OHE in patients with cirrhosis. In this prospective, double-blind, randomized, placebo-controlled trial conducted at two tertiary care institutes in India, 370 patients with cirrhosis and bouts of OHE were screened. After exclusion, 193 (52.16%) patients were randomized to receive either intravenous infusions of LOLA (n = 98), 30 g daily, or placebo (n = 95) for 5 days. Standard of care treatment (including lactulose and ceftriaxone) was given in both groups. Randomization was done centrally (http://www.sealedenvelope.com/). All study personnel were blinded to the treatment assignment. Fasting venous ammonia levels were estimated daily from 0 to 5 days. Serum tumor necrosis factor-alpha, interleukins, hemogram, and liver and renal function tests were performed at days 0 and 5. Primary outcome was mental state grade at day 5 of treatment. The grade of OHE was significantly lower in the LOLA group (compared to placebo) on days 1-4 but not on day 5. The mean time taken for recovery was lower in the LOLA group compared to the placebo group (1.92 ± 0.93 versus 2.50 ± 1.03 days, P = 0.002; 95% confidence interval -0.852 to -0.202). Venous ammonia at day 5 and length of hospital stay were significantly lower in the LOLA group. No significant difference in interleukins was seen between the groups. Conclusion: In patients with bouts of OHE, intravenous LOLA (as an add-on therapy to lactulose and ceftriaxone) significantly improves the grade of OHE over days 1-4, but not on day 5, and decreases venous ammonia, time of recovery, and length of hospital stay. (Hepatology 2018;67:700-710).

Circulating monocytes accelerate acute liver failure by IL-6 secretion in monkey.

Acute liver failure (ALF) is associated with high mortality, and a poor understanding of the underlying pathophysiology has resulted in a lack of effective treatments so far. Here, using an amatoxin-induced rhesus monkey model of ALF, we panoramically revealed the cellular and molecular events that lead to the development of ALF. The challenged monkeys with toxins underwent a typical course of ALF including severe hepatic injury, systemic inflammation and eventual death. Adaptive immune was not noticeably disturbed throughout the progress of ALF. A systematic examination of serum factors and cytokines revealed that IL-6 increase was the most rapid and drastic. Interestingly, we found that IL-6 was mainly produced by circulating monocytes. Furthermore, ablation of monocyte-derived IL-6 in mice decreased liver injury and systemic inflammation following chemical injection. Our findings reveal a critical role of circulating monocytes in initiating and accelerating ALF, indicating a potential therapeutic target in clinical treatment for ALF.

Systemic inflammation without gliosis mediates cognitive deficits through impaired BDNF expression in bile duct ligation model of hepatic encephalopathy.

Chronic liver disease per se induces neuroinflammation that contributes to cognitive deficits in hepatic encephalopathy (HE). However, the processes by which pro-inflammatory molecules result in cognitive impairment still remains unclear. In the present study, a significant increase in the activity of liver function enzymes viz. alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) was observed along with increase in plasma ammonia levels after four weeks of bile duct ligation (BDL) in rats suggesting hepatocellular damage. A significant increase was observed in mRNA expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) in brain regions and liver of BDL rats. Concomitantly, IL-6, TNF-α and MCP-1 protein levels were also increased in brain regions, liver and serum of BDL rats suggesting the involvement of blood-brain-axis in inflammatory response. However, a significant decrease was observed in glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (Iba-1) expression at transcriptional and translation level in brain of BDL rats. Immunohistochemical and flowcytometric analysis revealed reduced number of GFAP-immunopositive astrocytes and Iba1-immunopositive microglia in the brain regions of BDL rats. Further, a significant decline was observed in cognitive functions in BDL rats assessed using Morris water maze and novel object recognition tests. Expression of pro and mature form of brain derived neurotrophic factor (BDNF) and its upstream transcription element showed significant reduction in brain of BDL rats. Taken together, the results of the present study suggest that systemic inflammation and reduced expression of BDNF and its upstream transcription factor plays a key role in cognitive decline in HE.

[Immune status of liver failure patients and related immune regulation therapy].

Liver failure refers to a series of clinical syndromes manifesting as coagulation disorders, jaundice, hepatic encephalopathy, ascites, and other decompensated abnormalities due to serious hepatic dysfunction or decompensation in terms of synthesis, detoxification, excretion, and biological transformation caused by a variety of factors. In recent years, with the development of the research on immunological pathogenesis of liver failure, the "three-hit" theory clarifies the pathogenesis of liver failure. Major therapeutic strategies for liver failure are to prevent hepatocyte necrosis, promote hepatocyte regeneration, create a good internal environment for hepatocyte regeneration, and actively prevent and treat complications. An understanding of the immune status of liver failure patients and early application of glucocorticoids at right timing may help to improve prognosis and reduce adverse reactions. Establishment of a quantitative or functional balance between different cell subsets and new thoughts on some key cytokines may provide new directions and targets for immune regulation of liver failure.

ESTIMATION OF THE CYTOKINS LEVEL IN EXPERIMENTAL HEPATIC ENCEPHALOPATHY IN RATS.

Connection of the cytokins profile with experimental hepatic encephalopathy (HE) in rats was studied. Investigation was conducted on 20 laboratory rats, in which HE was simulated, using СCl4 injection. The іnterleukins (ІL) level, including, ІL­1ß, ІL­4, ІL­10 and interferon­Î³(IFN­Î³), was determined using immunoassay method with the help of polyclonal antibodies. Enhancement of the proinflammatory ІL­1ß and ІНФ­Î³ content in the rats blood serum while induced HE by 57.9 and 39.5% accordingly (p <0.05), comparing with such in a control and the compensation enhancement of the anti'inflammatory IL­4 and IL­10 level by 34.6 and 75.9% (p < 0.05) was established. The results obtained confirms the cytokins role in pathogenesis of HE, determination of their level constitutes significant criterion for the posttransplantation complications prog' nostication. Inflammation and profile of cytokins constitute the main target in therapy of HE in patients, suffering liver cirrhosis

Inflammation and hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with both acute and chronic liver dysfunction, spanning a spectrum that ranges from mild neuropsychological disturbances to coma. The central role of ammonia in the pathogenesis of HE remains incontrovertible however, there is a robust evidence base indicating the important role of inflammation in exacerbating the neurological effects of HE. Inflammation can arise directly within the brain itself as a result of deranged nitrogen and energy homeostasis, with resultant neuronal, astrocyte and microglial dysfunction. Inflammation may also originate in the peripheral circulation and exert effects on the brain indirectly, via the release of pro-inflammatory mediators which directly signal to the brain via the vagus nerve. This review summarises the data that demonstrate the synergistic relationship of inflammation and ammonia that culminates in the manifestation of HE. Sterile inflammation arising from the inflamed or necrotic liver, circulating endotoxin arising from the gut (bacterial translocation) inducing immune dysfunction, and superimposed sepsis will be comprehensively discussed. Finally, this review will provide an overview of the existing and novel treatments on the horizon which can target the inflammatory response, and how they might translate into clinical practise as therapies in the prophylaxis and treatment of HE.

Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy.

BACKGROUND & AIMS: Hyperammonemia and inflammation cooperate to induce neurological alterations in hepatic encephalopathy. Recent studies in animal models suggest that chronic hyperammonemia and neuroinflammation impair learning ability by the same mechanism. Chronic hyperammonemia might induce inflammatory factors in the brain that impair cognitive function. We sought to determine whether hyperammonemia itself induces neuroinflammation, whether ammonia-induced neuroinflammation mediates cognitive impairment, and whether neuroinflammation also occurs in rats with bile duct ligation (BDL rats)-a model of chronic liver injury that results in hyperammonemia and hepatic encephalopathy. METHODS: Chronic moderate hyperammonemia was induced by feeding male Wistar rats an ammonium-containing diet or performing BDL. Rats that received a standard diet or a sham operation were used as controls. Neuroinflammation was assessed by measuring activation of microglia and inflammatory factors. Brain samples were collected from hyperammonemic and BDL rats; microglial activation was determined by immunohistochemistry and quantification of inflammatory markers (ie, inducible nitric oxide synthase, interleukin-1beta, and prostaglandin E2). Learning ability and motor activity were assessed in hyperammonemic and BDL rats given ibuprofen as an anti-inflammatory agent. RESULTS: Chronic moderate hyperammonemia or BDL activated the microglia, especially in cerebellum; increased inducible nitric oxide synthase, interleukin-1beta, and prostaglandin E2 levels; and impaired cognitive and motor function, compared with controls. Ibuprofen reduced microglial activation and restored cognitive and motor functions in the hyperammonemic and BDL rats. CONCLUSIONS: Chronic hyperammonemia is sufficient to induce microglial activation and neuroinflammation; these contribute to the cognitive and motor alterations that occur during hepatic encephalopathy.

Essential roles of the Fas ligand in the development of hepatitis.

The Fas ligand (FasL) is expressed in activated T cells and induces apoptosis in Fas-bearing cells. A cytotoxic T lymphocyte (CTL) clone specific for hepatitis B surface antigen (HBsAg) causes an acute liver disease in HBsAg transgenic mice. Here we observed that the CTL clone killed hepatocytes expressing HBsAg in a Fas-dependent manner. Administration of the soluble form of Fas into HBsAg transgenic mice prevented the CTL-induced liver disease. In the second model, mice were primed with Propionibacterium acnes. A subsequent challenge with lipopolysaccharide (LPS) killed the mice by inducing liver injury. Neutralization of FasL rescued the mice from LPS-induced mortality, and Fas-null mice were resistant to LPS-induced mortality. These results suggest that FasL has an essential role in the development of hepatitis.

Pro-inflammatory cytokines are raised in extrahepatic portal venous obstruction, with minimal hepatic encephalopathy.

BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) and hyperammonemia are seen in patients with extrahepatic portal venous obstruction (EHPVO). Inflammation has been shown to play an important role in the pathogenesis of hepatic encephalopathy in cirrhotics. This study assessed serum pro-inflammatory cytokines and their correlation with hyperammonemia, (1)H-magnetic resonance (MR) spectroscopy-derived brain glutamine, and diffusion tensor imaging (DTI)-derived metrics in patients with EPHVO, with and without MHE. METHODS: Neuropsychological tests, DTI, (1)H-MR spectroscopy, and estimation of blood ammonia and pro-inflammatory cytokines (tumor necrosis factor-α[TNF-α] and interleukin-6 [IL-6]) were done in 20 patients with EHPVO and eight healthy controls. RESULTS: Pro-inflammatory cytokines (TNF-α and IL-6), blood ammonia, brain glutamine, and mean diffusivity were increased in both patient groups, as compared to controls. Patients with MHE (n-12) had significantly higher TNF-α, IL-6, blood ammonia, brain glutamine, and mean diffusivity, signifying brain edema, than controls. A significant, positive correlation was seen between TNF-α and IL-6 and between blood ammonia and TNF-α, IL-6, and brain glutamine. Significant, positive correlations of TNF-α, IL-6, and blood ammonia with mean diffusivity values were seen in various brain regions, including spectroscopy voxel-derived mean diffusivity. CONCLUSION: Patients with extrahepatic portal vein obstruction have inflammation and hyperammonemia made evident by higher blood TNF-α, IL-6, ammonia, and brain glutamine levels. A significant correlation between hyperammonemia, pro-inflammatory cytokines, and cerebral edema on DTI in various brain regions suggests that both these factors play a role in the pathogenesis of MHE in these patients.

The relation between pathogenesis of liver cirrhosis, hepatic encephalopathy and serum cytokine levels: what is the role of tumor necrosis factor α?

BACKGROUND/AIMS: Hepatic encephalopathy (HE) is a major complication of acute or chronic liver disease characterized by neuropsychiatric symptoms. It's etiology and pathogenetical mechanisms are not clearly understood and probably it is multifactorial. In this study, we aimed to investigate the relation between pathogenesis of HE and TNF-alpha, IL-1beta, IL-2R, IL-6, IL-8 and IL-10, and between the severity of HE and the levels of these cytokines. METHODOLOGY: Eighty patients with liver cirrhosis [50 patients with clinical findings of HE (group 1) and 30 without any symptoms of HE (group 2)] and 30 healthy controls (group 3) were included into the study. Serum TNF-alpha, IL-1beta, IL-2R, IL-6, IL-8 and IL-10 levels of patients and control subjects were studied with the chemiluminescent method. RESULTS: There were statistically significant difference between serum TNF-alpha, IL-1beta, IL-2R, IL-6 and IL-8 levels of patients with liver cirrhosis and healthy subjects (p<0.05), and between patients with and without HE (p<0.05). There was a correlation between the severity of liver cirrhosis according to Child-Pugh classification and cytokine levels. The severity of HE (grade 1-4) was closely related with cytokine levels, especially TNF-a. On the other hand, there was no relation between cytokine levels and the etiological factors. CONCLUSION: We found a positive correlation between serum inflammatory cytokine levels (TNF-alpha, IL-1beta, IL-2R, IL-6, IL-8) and the severity of liver cirrhosis. In addition, our findings suggested that this relation is independent from etiological factors.

Dexmedetomidine alleviates neuroinflammation, restores sleep disorders and neurobehavioral abnormalities in rats with minimal hepatic encephalopathy.

The occurrence and progress of minimal hepatic encephalopathy (MHE) is closely related to the inflammatory response; however, inflammation contributes to behavioral abnormalities and sleep disorders. Dexmedetomidine has anti-inflammatory effects against various diseases. Whether dexmedetomidine improves MHE and the underlying mechanism is yet unclear. The present study aimed to explore the effects of dexmedetomidine on sleep structure, neurobehavior, and brain morphology of MHE rats and investigate its underlying mechanism. A rat MHE model was established by intraperitoneal injection of thioacetamide (TAA). Dexmedetomidine or yohimbine was administered intraperitoneally to investigate the role of α2 adrenoreceptor in the protection conferred by dexmedetomidine. The 24-h sleep, neurobehavioral changes, the liver function, blood ammonia and morphological changes of the liver and brain were assessed. Also, the microglia, astrocytes, neurons, the expression of pro-inflammatory factors (IL-1ß, TNF-α, IL-18), and NLRP3 inflammasomes were detected. The results showed that marked sleep disorders, cognitive impairment, anxiety, abnormal liver function and pathological damage of liver and brain were detected in the MHE rats. The microglia in the prefrontal cortex was highly activated along with the increased expression of pro-inflammatory factors and NLRP3 inflammasomes. Interestingly, dexmedetomidine improved above indicators, however, yohimbine significantly abolished the protection of dexmedetomidine. These findings showed that dexmedetomidine restored the changes in the sleep disorders and neurobehavior in rats and reduced brain damage. The mechanism might be partially related to the activation of α2 adrenergic receptors, reduction of neuroinflammatory response, and inhibition of the activation of microglia and NLRP3/Caspase1 signaling pathway.

Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis.

The molecular and cellular mechanisms responsible for cytotoxic T lymphocyte (CTL)-induced immunopathology are not well defined. Using a model in which hepatitis B surface antigen (HBsAg)-specific CTL cause an acute necroinflammatory liver disease in HBsAg transgenic mice, we demonstrate that class I-restricted disease pathogenesis is an orderly, multistep process that involves direct as well as indirect consequences of CTL activation. It begins (step 1) almost immediately as a direct antigen-specific CTL-target cell interaction that triggers the HBsAg-positive hepatocyte to undergo programmed cell death (apoptosis). It progresses (step 2) within hours to a focal inflammatory response in which antigen-nonspecific lymphocytes and neutrophils amplify the local cytopathic effect of the CTL. The most destructive pathogenetic function of the CTL, however, is to secrete interferon gamma when they encounter antigen in vivo, thereby activating the intrahepatic macrophage and inducing a delayed-type hypersensitivity response (step 3) that destroys the liver and kills the mouse. We propose that the principles illustrated in this study are generally applicable to other models of class I-restricted, CTL-induced immunopathology, and we suggest that they contribute to the immunopathogenesis of viral hepatitis during hepatitis B virus infection in humans.

Ameliorative effect of Magnesium Isoglycyrrhizinate on hepatic encephalopathy by Epirubicin.

BACKGROUND: The purpose of the present study was to evaluate the protective effect of Magnesium Isoglycyrrhizinate (MI) on Epirubicin (EPI)-induced hepatic encephalopathy (HE) and explore its underlying mechanism. METHODS: Mice were divided randomly into groups for treatments as follows: control group, EPI group (Model group), EPI + MI (25, 50 mg/kg) group. Morris water maze test were conducted to evaluate the spatial learning and memory ability. The serum and hippocampus levels of oxidative stress or inflammation were uncovered with the detection of superoxide dismutase (SOD), malondialdehyde (MDA), and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α). RESULTS: As a result, treatment with MI effectively ameliorated the EPI-induced decline in the ability of spatial learning and memory. MI also significantly relieved the severity of oxidative stress or inflammation in serum and hippocampus, which was accompanied with regulating liver functional parameters. Western blot data demonstrated that administration of MI could regulate the redox-related expressions of Txnip, Trx, Nrf2, HO-1, p-IκB-α, p-NF-κB, Caspase-3, Caspase-9, Bax and Bcl-2 in EPI-stimulated hepatic encephalopathy (HE). And the potency of MI treatments on Nrf2, NF-κB expression was also confirmed with immunohistochemical analysis. CONCLUSIONS: Taken together, the protective effect of Magnesium Isoglycyrrhizinate on EPI-induced hepatic encephalopathy might be mediated via the Txnip/Nrf2/NF-κB signaling pathway.

Superinfective Hepatitis E Virus Infection Aggravates Hepatocytes Injury in Chronic Hepatitis B.

Hepatitis E virus (HEV) infection is a major cause of morbidity in endemic areas. Its consequences among chronic hepatitis B (CHB) patients have been under-reported. The aim of this study was to assess the impact of superinfective HEV infection (acute and past) on virological and clinical features of patients with CHB infection. Clinical, biochemical, virological and immunological data of 153 CHB patients including 98 with hepatitis B virus (HBV) monoinfection and 55 with HBV-HEV superinfection with both HEV and HBV infection was retrospectively investigated and analyzed in this study conducted in Wuhan, China. An overall anti-HEV IgG seroprevalence was found to be 35.9% in CHB patients. HBV-HEV superinfection patients showed significantly higher rate of complications (ascites, hepato-renal syndrome & encephalopathy) (all with P=0.04), cirrhosis (P<0.001) and acute-on-chronic liver failure (P<0.001) than HBV monoinfection patients. They also displayed elevated ALTs (P<0.001) and total serum bilirubin (P<0.001) with diminished albumin (P<0.001) and HBV viral load (P<0.001). Cytokines assay revealed increased expression of IL-6 (P=0.02), IL-10 (P=0.009) and TNF-α (P=0.003) in HBV-HEV superinfection patients compared to HBV monoinfection patients. Our study demonstrated that HEV superinfection in CHB patients was associated with progressive clinical manifestation, which is likely due to the enhanced expression of cytokines related with hepatocytes necrosis. HEV was also associated with repressed HBV replication, but the underlying mechanism requires further investigation.

The mast cell integrates the splanchnic and systemic inflammatory response in portal hypertension.

Portal hypertension is a clinical syndrome that is difficult to study in an isolated manner since it is always associated with a greater or lesser degree of liver functional impairment. The aim of this review is to integrate the complications related to chronic liver disease by using both, the array of mast cell functions and mediators, since they possibly are involved in the pathophysiological mechanisms of these complications. The portal vein ligated rat is the experimental model most widely used to study this syndrome and it has been considered that a systemic inflammatory response is produced. This response is mediated among other inflammatory cells by mast cells and it evolves in three linked pathological functional systems. The nervous functional system presents ischemia-reperfusion and edema (oxidative stress) and would be responsible for hyperdynamic circulation; the immune functional system causes tissue infiltration by inflammatory cells, particularly mast cells and bacteria (enzymatic stress) and the endocrine functional system presents endothelial proliferation (antioxidative and antienzymatic stress) and angiogenesis. Mast cells could develop a key role in the expression of these three phenotypes because their mediators have the ability to produce all the aforementioned alterations, both at the splanchnic level (portal hypertensive enteropathy, mesenteric adenitis, liver steatosis) and the systemic level (portal hypertensive encephalopathy). This hypothetical splanchnic and systemic inflammatory response would be aggravated during the progression of the chronic liver disease, since the antioxidant ability of the body decreases. Thus, a critical state is produced, in which the appearance of noxious factors would favor the development of a dedifferentiation process protagonized by the nervous functional system. This system rapidly induces an ischemia-reperfusion phenotype with hydration and salinization of the body (hepatorenal syndrome, ascites) which, in turn would reduce the metabolic needs of the body and facilitate its temporary survival.

Minimal hepatic encephalopathy is associated with expansion and activation of CD4+CD28-, Th22 and Tfh and B lymphocytes.

Peripheral inflammation acts synergistically with hyperammonemia in inducing neurological alterations in cirrhotic patients with minimal hepatic encephalopathy (MHE). We hypothesized that appearance of MHE would be associated to some specific qualitative change in peripheral inflammation. The aim of this work was to characterize the changes in peripheral inflammation associated to appearance of MHE. We analyzed it by immunophenotyping and cytokine profile analysis, in cirrhotic patients without or with MHE and controls. The main alterations associated specifically with MHE are: 1) increased activation of all subtypes of CD4+ T-lymphocytes, with the increased expression of CD69; 2) increased amount of CD4+CD28- T lymphocytes, associated with increased levels of CX3CL1 and of IL-15; 3) increased differentiation of CD4+ T lymphocytes to Th follicular and Th22; 4) increased activation of B lymphocytes and serum IgG. This study has identified some specific alterations of the immune system associated with appearance of the neurological alterations in MHE patients.