Portocaval shunt can optimize transhepatic flow following extended hepatectomy: a short-term study in a porcine model.

The aim of this study was to evaluate whether the portocaval shunt (PCS) corrects these unwanted changes in transhepatic flow after extended hepatectomy (EH). Forty female Landrace pigs were divided into two main groups: (A) EH (75%) and (B) no EH. Group A was divided into 3 subgroups: (A1) EH without PCS; (A2) EH with side-to-side PCS; and (A3) EH with end-to-side PCS. Group B was divided into 2 subgroups: (B1) side-to-side PCS and (B2) end-to-side PCS. HAF, PVF, and PVP were measured in each animal before and after the surgical procedure. EH increased the PVF/100 g (173%, p < 0.001) and PVP (68%, p < 0.001) but reduced the HAF/100 g (22%, p = 0.819). Following EH, side-to-side PCS reduced the increased PVF (78%, p < 0.001) and PVP (38%, p = 0.001). Without EH, side-to-side PCS reduced the PVF/100 g (68%, p < 0.001) and PVP (12%, p = 0.237). PVP was reduced by end-to-side PCS following EH by 48% (p < 0.001) and without EH by 21% (p = 0.075). PCS can decrease and correct the elevated PVP and PVF/100 g after EH to close to the normal values prior to resection. The decreased HAF/100 g in the remnant liver following EH is increased and corrected through PCS.

Is Portal Inflow Modulation Always Necessary for Successful Utilization of Small Volume Living Donor Liver Grafts?

Although the well-accepted lower limit of the graft-to-recipient weight ratio (GRWR) for successful living donor liver transplantation (LDLT) remains 0.80%, many believe grafts with lower GRWR may suffice with portal inflow modulation (PIM), resulting in equally good recipient outcomes. This study was done to evaluate the outcomes of LDLT with small-for-size grafts (GRWR <0.80%). Of 1321 consecutive adult LDLTs from January 2012 to December 2017, 287 (21.7%) had GRWR <0.80%. PIM was performed (hemiportocaval shunt [HPCS], n = 109; splenic artery ligation [SAL], n = 14) in 42.9% patients. No PIM was done if portal pressure (PP) in the dissection phase was <16 mm Hg. Mean age of the cohort was 49.3 ± 9.1 years. Median Model for End-Stage Liver Disease score was 14, and the lowest GRWR was 0.54%. A total of 72 recipients had a GRWR <0.70%, of whom 58 underwent HPCS (1 of whom underwent HPCS + SAL) and 14 underwent no PIM, whereas 215 had GRWR between 0.70% and 0.79%, of whom 51 and 14 underwent HPCS and SAL, respectively. During the same period, 1034 had GRWR ≥0.80% and did not undergo PIM. Small-for-size syndrome developed in 2.8% patients. Three patients needed shunt closure at 1 and 4 weeks and 60 months. The 1-year patient survival rates were comparable. In conclusion, with PIM protocol that optimizes postperfusion PP, low-GRWR grafts can be used for appropriately selected LDLT recipients with acceptable outcomes.

Impact of Temporary Portocaval Shunting and Initial Arterial Reperfusion in Orthotopic Liver Transplantation.

The use of a temporary portocaval shunt (TPCS) as well as the order of reperfusion (initial arterial reperfusion [IAR] versus initial portal reperfusion) in orthotopic liver transplantation (OLT) is controversial and, therefore, still under debate. The aim of this study was to evaluate outcome for the 4 possible combinations (temporary portocaval shunt with initial arterial reperfusion [A+S+], temporary portocaval shunt with initial portal reperfusion, no temporary portocaval shunt with initial arterial reperfusion, and no temporary portocaval shunt with initial portal reperfusion) in a center-based cohort study, including liver transplantations (LTs) from both donation after brain death and donation after circulatory death (DCD) donors. The primary outcome was the perioperative transfusion of red blood cells (RBCs), and the secondary outcomes were operative time and patient and graft survival. Between January 2005 and May 2017, all first OLTs performed in our institution were included in the 4 groups mentioned. With IAR and TPCS, a significantly lower perioperative transfusion of RBCs was seen (P < 0.001) as well as a higher number of recipients without any transfusion of RBCs (P < 0.001). A multivariate analysis showed laboratory Model for End-Stage Liver Disease (MELD) score (P < 0.001) and IAR (P = 0.01) to be independent determinants of the transfusion of RBCs. When comparing all groups, no statistical difference was seen in operative time or in 1-year patient and graft survival rates despite more LTs with a liver from a DCD donor in the A+S+ group (P = 0.005). In conclusion, next to a lower laboratory MELD score, the use of IAR leads to a significantly lower need for perioperative blood transfusion. There was no significant interaction between IAR and TPCS. Furthermore, the use of a TPCS and/or IAR does not lead to increased operative time and is therefore a reasonable alternative surgical strategy.

Passive mesenterico-saphenous shunt: An alternative to portocaval anastomosis for tailored portal decompression during liver transplantation.

BACKGROUND: Temporary portocaval shunt has a positive impact on short-term outcomes after liver transplantation. An alternative to temporary portocaval shunt is a distal passive decompression through mesenterico-saphenous shunt. The purpose of this study was to compare outcomes of these two types of surgical portosystemic shunt and discuss their respective place during the anhepatic phase. METHODS: Patients transplanted with portal decompression during a 4-year period were included. Patients were compared according to two types of surgical decompression techniques: temporary portocaval shunt (n = 44) and mesenterico-saphenous shunt (n = 77). Spontaneous >5-mm portosystemic shunts were described as absent, nonpersistent, distal, or proximal. Intraoperative portal pressure variations and inhospital course were compared between the two groups, with special attention on the impact of competing spontaneous and surgical shunts. RESULTS: Mesenterico-saphenous shunt and temporary portocaval shunt showed a comparable hemodynamic efficiency, with no significant difference in terms of portal pressure variations. We found no significant difference in terms of reperfusion syndrome (P = .956), transfusion rate (P = .575), renal failure (P = .239) nor early allograft dysfunction (P = .976). There was a significantly higher risk of early allograft dysfunction when competing surgical and spontaneous shunts were used (P = .002) with a lesser hemodynamic efficiency (analysis of variance test; P = .04). CONCLUSION: Portacaval or mesenterico-saphenous shunts offer similar hemodynamic efficiency without impacting the outcomes after liver transplantation. Their respective place and the place of portal decompression should be discussed regarding the presence of portal thrombosis and pre-existing portosystemic shunts. Evaluation of the anatomy and the efficiency of these shunts may guide tailored portal decompression.

Pediatric Budd-Chiari Syndrome: A Case Series.

OBJECTIVE: To study the diagnostic methods and treatment outcomes in children with Budd- Chiari syndrome. METHODS: Case records of 25 patients with Budd-Chiari syndrome were evaluated retrospectively. These patients were investigated with imaging techniques and underwent balloon angioplasty or surgical management. RESULTS: 21 patients underwent balloon angioplasty, of which 17 had good medium- to long-term results, while only one out of four patients who underwent a portocaval shunt survived. CONCLUSIONS: The balloon angioplasty has satisfactory outcome in the treatment of acute Budd-Chiari syndrome. In failed cases, the surgical therapy may be attempted, but the outcomes do not appear rewarding.

Portacaval shunting causes differential mitochondrial superoxide production in brain regions.

The portacaval shunting (PCS) prevents portal hypertension and recurrent bleeding of esophageal varices. On the other hand, it can induce chronic hyperammonemia and is considered to be the best model of mild hepatic encephalopathy (HE). Pathogenic mechanisms of HE and dysfunction of the brain in hyperammonemia are not fully elucidated, but it was originally suggested that the pathogenetic defect causes destruction of antioxidant defense which leads to an increase in the production of reactive oxygen species (ROS) and the occurrence of oxidative stress. In order to gain insight into the pathogenic mechanisms of HE in the brain tissue, we investigated the effects of PCS in rats on free radicals production and activity levels of antioxidant and prooxidant enzymes in mitochondria isolated from different brain areas. We found that O2·- production, activities of Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione transferase (GT), nitric oxide synthase (NOS), and levels of carbonylated proteins differed between the four brain regions both in the amount and response to PCS. In PCS rats, Mn-SOD activity in the cerebellum was significantly decreased, and remained unchanged in the neocortex, hippocampus and striatum compared with that in sham-operated animals. Among the four brain regions in control rats, the levels of the carbonyl groups in mitochondrial proteins were maximal in the cerebellum. 4 weeks after PCS, the content of carbonylated proteins were higher only in mitochondria of this brain region. Under control conditions, O2·- production by submitochondrial particles in the cerebellum was significantly higher than in other brain regions, but was significantly increased in each brain region from PCS animals. Indeed, the production of O2·- by submitochondrial particles correlated with mitochondrial ammonia levels in the four brain regions of control and PCS-animals. These findings are the first to suggest that in vivo levels of ammonia in the brain directly affect the rate of mitochondrial O2·- production.

Reappraisal of the Role of Portacaval Shunting in the Growth of Patients With Glycogen Storage Disease Type I in the Era of Liver Transplantation.

BACKGROUND: Instead of dietary modification, surgical management is considered for correcting growth retardation, poor metabolic control, and hepatocellular adenoma (HCA) in glycogen storage disease (GSD) type I. METHODS: The records of 55 GSD type I patients were retrospectively reviewed. Thirty-two patients underwent only dietary management (group D) and 23 underwent surgical management (group S). In group S, 17 underwent portacaval shunting (PCS), 13 underwent liver transplantation (LT; 7 underwent both PCS and LT). Height-for-age and body mass index-for-age Z-scores based on World Health Organization data were used to compare growth patterns before and after surgery. Changes in metabolic abnormalities and HCA after operation were also investigated. RESULTS: Height-for-age Z-scores for group S were higher by an average of 0.377 compared to that for group D. Metabolic abnormalities often disappeared after LT but improved partially after PCS. De novo HCA was detected in 4 patients (13%) from group D, 12 (100%) who underwent PCS, and none who underwent LT. One case of hepatocellular carcinoma and one of hemorrhage from a HCA were noted in group D. Two cases of hepatocellular carcinoma, 2 of hemorrhage, and 1 of necrosis were noted after PCS. CONCLUSIONS: Surgery yielded greater growth improvement than dietary management. However, after PCS, metabolic abnormalities remained unresolved, and the de novo HCA rate was high. Portacaval shunting can be used to improve growth in GSD type I patients when LT is not possible, but close observation for metabolic abnormalities and HCA is essential.

The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients.

BACKGROUND: Liver failure in experimental animals or in human cirrhosis elicits neuroinflammation. Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory events in neurodegenerative diseases: PREP protein levels are increased in brain glial cells upon neuroinflammatory insults, but the circulating PREP activity levels are decreased in multiple sclerosis patients in a process probably mediated by bioactive peptides. In this work, we studied the variation of PREP levels upon liver failure and correlated it with several inflammatory markers to conclude on the relation of PREP with systemic and/or neuroinflammation. METHODS: PREP enzymatic activity and protein levels measured with immunological techniques were determined in the brain and plasma of rats with portacaval shunt (PCS) and after treatment with ibuprofen. Those results were compared with the levels of PREP measured in plasma from cirrhotic patients with or without minimal hepatic encephalopathy (MHE). Levels of several pro-inflammatory cytokines and those of NO/cGMP homeostasis metabolites were measured in PCS rats and cirrhotic patients to conclude on the role of PREP in inflammation. RESULTS: In PCA rats, we found that PREP levels are significantly increased in the hippocampus, striatum and cerebellum, that in the cerebellum the PREP increase was significantly found in the extracellular space and that the levels were restored to those measured in control rats after administration of an anti-inflammatory agent, ibuprofen. In cirrhotic patients, circulatory PREP activity was found to correlate to systemic and neuroinflammatory markers and had a negative correlation with the severity of the disease, although no clear relation to MHE. CONCLUSIONS: These results support the idea that PREP levels could be used as indicators of cirrhosis severity in humans, and using other markers, it might contribute to assessing the level of neuroinflammation in those patients. This work reports, for the first time, that PREP is secreted to the extracellular space in the cerebellum most probably due to glial activation and supports the role of the peptidase in the inflammatory response.

Emergent salvage direct intrahepatic portocaval shunt procedure for acute variceal hemorrhage.

PURPOSE: To review the safety and effectiveness of direct intrahepatic portocaval shunt (DIPS) creation with variceal embolization for acute variceal hemorrhage after a failed transjugular intrahepatic portosystemic shunt (TIPS) creation attempt or in patients with prohibitive anatomy. MATERIALS AND METHODS: Transjugular intrahepatic portosystemic shunt and DIPS procedures performed for variceal hemorrhage between January 2008 and July 2014 were reviewed. The default procedure was TIPS creation, with DIPS creation reserved for patients with unfavorable anatomy or who had technically unsuccessful TIPS creation. Thirteen patients underwent DIPS creation (mean age, 60 y ± 12; Child-Pugh class A/B/C, 8%/62%/30%; Model for End-stage Liver Disease score, 15 ± 5; range, 8-26) and 117 underwent TIPS creation. Four patients underwent a TIPS attempt and were converted to DIPS creation upon technical failure; 9 were treated primarily with DIPS creation because of preprocedural imaging revealing unfavorable anatomy (intrahepatic portal thrombosis, n = 2; venous distortion from prior hepatic resections, n = 2; severely angulated hepatic veins, n = 5). RESULTS: Direct intrahepatic portocaval shunt creation with variceal embolization (six gastric or esophageal; seven stomal, duodenal, or rectal) was successful in all patients; 11 also had concomitant variceal sclerotherapy. Mean DIPS procedure time was less than 2 hours. There was 1 major procedural complication. During a mean follow-up of 13.0 months ± 15.5, 1 patient developed DIPS thrombosis and recurrent hemorrhage; 1 patient underwent successful transplantation. Two deaths were observed within 30 days, neither associated with recurrent hemorrhage. CONCLUSIONS: Direct intrahepatic portocaval shunt creation appears to be a safe, expedient, and effective treatment for patients with acute variceal hemorrhage who are poor anatomic candidates for TIPS creation or who have undergone unsuccessful TIPS creation attempts.

Should temporary extracorporeal continuous portal diversion replace meso/porta-caval shunts in "small-for-size" syndrome in porcine hepatectomy?

AIM: To investigate the feasibility of temporary extracorporeal continuous porta-caval diversion (ECPD) to relieve portal hyperperfusion in "small-for-size" syndrome following massive hepatectomy in pigs. METHODS: Fourteen pigs underwent 85%-90% liver resection and were then randomly divided into the control group (n = 7) and diversion group (n = 7). In the diversion group, portal venous blood was aspirated through the portal catheter and into a tube connected to a centrifugal pump. After filtration, the blood was returned to the pig through a double-lumen catheter inserted into the internal jugular or subclavian vein. With the conversion pump, portal venous inflow was partially diverted to the inferior vena cava through a catheter inserted via the gastroduodenal vein at 100-130 mL/min. Portal hemodynamics, injury, and regeneration in the liver remnant were compared between the two groups. RESULTS: Compared to the control group, porta-caval diversion via ECPD significantly mitigated excessive portal venous flow and portal vein pressure (PVP); the portal vein flow (PVF), hepatic artery flow (HAF), and PVP in the two groups were not significantly different at baseline; however, the PVF (431.8 ± 36.6 vs 238.8 ± 29.3, P < 0.01; 210.3 ± 23.4 vs 122.3 ± 20.6, P < 0.01) and PVP (13.8 ± 2.6 vs 8.7 ± 1.4, P < 0.01; 15.6 ± 2.1 vs 10.1 ± 1.3, P < 0.05) in the control group were significantly higher than those in the diversion group, respectively. The HAF in the control group was significantly lower than that in the diversion group at 2 h and 48 h post hepatectomy, and ECPD significantly attenuated injury to the sinusoidal lining and hepatocytes, increased the regeneration index of the liver remnant, and relieved damage that the liver remnant suffered due to endotoxin and bacterial translocation. CONCLUSION: ECPD, which can dynamically modulate portal inflow, can reduce injury to the liver remnant and facilitate liver regeneration, and therefore should replace permanent meso/porta-caval shunts in "small-for-size" syndrome.

[Differences between cerebellum and hippocampus in antioxidant system].

The effect of portacaval shunting on the antioxidant status of the cerebellum and hippocampus was studied in rats using standard methods of enzymatic analysis. Endogenous ammonia levels and activities of eight antioxidant enzymes were shown to be unequal in two brain regions and to respond differently upon portal-systemic shunt surgery.

Hepatocyte transplants improve liver function and encephalopathy in portacaval shunted rats.

AIM: Rats with portacaval shunt (PCS) are useful experimental models of human hepatic encephalopathy in chronic liver dysfunction. We have previously shown that PCS modifies amine neurotransmitter systems in the CNS and increases voluntary alcohol intake by rats. Hepatocyte transplantation, used in acute liver failure, has recently also been applied to chronic liver diseases, which prompted us to investigate whether the altered brain amine system and the drinking behavior in long-term shunted rats could be normalized by hepatocyte transplants. METHODS: Hepatocytes, isolated from syngeneic donors by collagenase digestion, were injected (3 × 10(6) cells/rat) into the pancreatic tail region, 6 months after PCS. Hepatic function was evaluated by measuring urine urea and plasma L-histidine concentrations. A free choice test with two bottles (tap water and 10% ethyl alcohol) was performed for 3 days to assess the rats' preference for alcohol. The rats were euthanized 2 months posttransplantation. Brain histamine and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured by radioenzymatic assay and by HPLC-EC, respectively, N-tele-methylhistamine by GC/MS while MAOA and MAOB activities by isotopic procedures. RESULTS: Portacaval shunt rats with hepatocyte transplants gave more urea than before transplantation, with lower plasma L-His levels and higher body weight versus the PCS counterparts. Also, those rats consumed less alcohol. The CNS amines and 5-HIAA concentrations, as well as MAO-B activity, being abnormally high in untreated PCS rats, significantly reduced after PCS hepatocyte treatment. CONCLUSIONS: The results support the therapeutic values of hepatocyte transplants in chronic liver diseases and the temporary character of PCS-exerted CNS dysfunctions.

Rats with minimal hepatic encephalopathy due to portacaval shunt show differential increase of translocator protein (18 kDa) binding in different brain areas, which is not affected by chronic MAP-kinase p38 inhibition.

Neuroinflammation plays a main role in neurological deficits in rats with minimal hepatic encephalopathy (MHE) due to portacaval shunt (PCS). Treating PCS rats with SB239063, an inhibitor of MAP-kinase-p38, reduces microglial activation and brain inflammatory markers and restores cognitive and motor function. The translocator protein-(18-kDa) (TSPO) is considered a biomarker of neuroinflammation. TSPO is increased in brain of PCS rats and of cirrhotic patients that died in hepatic coma. Rats with MHE show strong microglial activation in cerebellum and milder in other areas when assessed by MHC-II immunohistochemistry. This work aims were assessing: 1) whether binding of TSPO ligands is selectively increased in cerebellum in PCS rats; 2) whether treatment with SB239063 reduces binding of TSPO ligands in PCS rats; 3) which cell type (microglia, astrocytes) increases TSPO expression. Quantitative autoradiography was used to assess TSPO-selective (3)H-(R)-PK11195 binding to different brain areas. TSPO expression increased differentially in PCS rats, reaching mild expression in striatum or thalamus and very high levels in cerebellum. TSPO was expressed in astrocytes and microglia. Treatment with SB239063 did not reduces (3)[H]-PK11195 binding in PCS rats. SB239063 reduces microglial activation and levels of inflammatory markers, but not binding of TSPO ligands. This indicates that SB239063-induced neuroinflammation reduction in PCS rats is not mediated by effects on TSPO. Also, enhanced TSPO expression is not always associated with cognitive or motor deficits. If enhanced TSPO expression plays a role in mechanisms leading to neurological alterations in MHE, SB239063 would interfere these mechanisms at a later step.

Reduced clearance of proteins labeled with diisopropylfluorophosphate in portacaval-shunted rats.

Portacaval shunting is a model for hepatic encephalopathy that causes chronic hyperammonemia, disruption of metabolic, signaling, and neurotransmitter systems, and progressive morphological changes. Exposure of cultured cells to ammonia raises intralysosomal pH and inhibits proteolysis, and the present study tested the hypothesis that proteolytic capacity is diminished in portacaval-shunted rats. Proteins were labeled in vivo with tracer doses of diisopropylfluorophosphate (DFP) and clearance of label was assayed. This approach labeled proteins independent of protein synthesis, which is reported to be altered in shunted rats, and avoided complications arising from re-utilization of labeled amino acids that causes underestimation of degradation rate. Characterization of DFP labeling showed that protein labeling was fast, about 50% of the label was released during a 24 h interval, labeling by DFP metabolites was negligible, inhibition of brain acetylcholinesterase was not detectable, and labeling by [(3)H]- and [(14)C]DFP was equivalent. To assay degradative capacity, proteins were first labeled with [(3)H]DFP, followed by labeling with [(14)C]DFP that was given 24 or 72 h later. The (3)H/(14)C ratio in each animal was used as a relative measure of removal of (3)H-labeled proteins. (3)H/(14)C ratios were generally significantly higher in portacaval-shunted rats than in controls, consistent with reduced proteolytic capacity. Assays of amino acid incorporation into brain protein generally replicated literature reports, supporting the conclusion that protein synthesis unlikely to be markedly inhibited and amino acid recycling influences calculated protein synthesis rates in shunted rats. Therapeutic strategies to reduce ammonia level would help normalize lysosomal functions and protein and lipid turnover.

Development of multiple focal nodular hyperplasia lesions after portocaval shunting. A case report.

It has been postulated that altered hepatic blood flow, particularly reduced portal flow, is responsible for the induction of hyperplasia of liver cells and nodule formation. This report describes the case of a 31-year old female patient developing multiple focal nodular hyperplasia (FNH) lesions two years after portocaval shunting and extended right hemihepatectomy due to the suspicion of a malignant liver tumor. Portocaval shunting became necessary due to iatrogenic thrombosis of the entire portal vein after preoperative embolization of the right portal vein. This observation provides for the first time direct evidence for the pathogenesis of FNH in humans.

Importance of the temporary portocaval shunt during adult living donor liver transplantation.

Adult living donor liver transplantation (aLDLT) is associated with surgical risks for the donor and with the possibility of small-for-size syndrome (SFSS) for the recipient, with both events being of great importance. An excessively small liver graft entails a relative increase in the portal blood flow during reperfusion, and this factor predisposes the recipient to an increased risk of SFSS in the postoperative period, although other causes related to recipient, graft, and technical factors have also been reported. A hemodynamic monitoring protocol was used for 45 consecutive aLDLT recipients. After various hemodynamic parameters before reperfusion were analyzed, a significant correlation between the temporary portocaval shunt flow during the anhepatic phase and the portal vein flow (PVF) after reperfusion of the graft (R(2) = 0.3, P < 0.001) was found, and so was a correlation between the native liver portal pressure and PVF after reperfusion (R(2) = 0.21, P = 0.007). The identification of patients at risk for excessive portal hyperflow will allow its modulation before reperfusion. This could favor the use of smaller grafts and ultimately lead to a reduction in donor complications because it would allow more limited hepatectomies to be performed.

Liver impairment after portacaval shunt in the rat: the loss of protective role of mast cells?

Mast cells are involved in various liver diseases and appear to play a broader pathogenic role than originally thought. They may participate in the splanchnic alterations related to a porto-systemic shunt. To verify this hypothesis we studied the serum and hepatic histological changes in rats four weeks after an end-to-side portacaval shunt. In this experimental model of chronic liver insufficiency we also assessed the mucosal mast cells (MMC) and connective tissue mast cells (CTMC) in the liver, mesenteric lymph nodes and small intestine, as well as the serum levels of rat mast cell protease-II (RMCP-II). The results show liver and testes atrophy, with hypoalbuminemia (p=0.0001), hyperbilirubinemia (p=0.0001) and increase in aspartate aminotransferase (p=0.004) and alanine aminotransferase (p=0.0001). Hepatic histopathology demonstrates hepatocytic necrosis and apoptosis, portal inflammation, biliary proliferation, steatosis and fibrosis. There is a decrease of MMCs and CTMCs in the liver, while in the ileum CTMCs increase and MMCs decrease. These results suggest the involvement of mast cells in the pathophysiological splanchnic impairments in this experimental model. In particular, the decreased number of liver mast cells may be associated with the hepatic atrophy. If this is the case, we propose that the disruption of the hepato-intestinal axis after a portocaval shunt in the rat could inhibit the ability of the liver to developing an appropriate repair response mediated by mast cells.

Exploratory investigation on nitro- and phospho-proteome cerebellum changes in hyperammonemia and hepatic encephalopathy rat models.

Hepatic encephalopathy (HE) is a neurological disease associated with hepatic dysfunction. Current knowledge suggests that hyperammonemia, related to liver failure, is a main factor contributing to the cerebral alterations in HE and that hyperammonemia might impair signal transduction associated with post-translational modification of proteins such as tyrosine-nitration and phosphorylation. However, the molecular bases of the HE remain unclear and very little is known about the occurrence of post-translational modification on in vivo proteins. In this exploratory study we look for evidence of post-translation modifications of proteins in the cerebellum of experimental HE rat models using a proteomic approach. For the first time we showed that hyperammonemia without liver failure (HA rats) and experimental HE with liver failure due to portacaval shunt (PCS rats) lead to a reduced protein nitration in rat cerebellum, where the undernitrated proteins were involved in energy metabolism and cytoskeleton remodelling. Moreover we showed that tyrosine nitration loss of these proteins was not necessarily associated to a change in their phosphorylation state as result of the disease. Interestingly the rat cerebellum phosphoproteome was mainly perturbed in PCS rats, whereas HA rats did not shown appreciable changes in their phosphoprotein profile. Since the protein nitration level decreased similarly in the cerebellum of both HA and PCS rats, this implies that the two disease models share common effects but also present some differential signalling effects in the cerebellum of the same animals. This study highlights the interest for studying the concerted action of multiple signalling pathways in HE development.