Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest...Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest altered functioning of the blood–brain barrier(BBB).Assessing BBB function is challenging in clinical practice and at the bedside.Protein-S-100 Beta(PS100-Beta)could be a useful peripheral marker of BBB permeability in HE.This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit(ICU)with decompensated cirrhosis with and without overt HE.Methods We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement.Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded.Overt HE was defined as West-Haven grades 2 to 4.The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes.After ICU discharge,the patients were followed for at least 3 months for the occurrence of overt HE.Adverse outcomes(liver transplantation or death)were collected.The ability of PS100-Beta–in combination with other factors–to predict overt HE was evaluated in a multivariate analysis using logistic regression.Likelihood ratios were used to determine the effects and calculate odds ratios(OR).Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test.Results A total of 194 ICU patients and 207 outpatients were included in the study.Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients([0.15±0.01]mg/L vs.[0.08±0]mg/L,P<0.001).ICU patients with overt HE had higher levels of PS100-Beta([0.19±0.03]mg/L)compared with the ICU patients without overt HE([0.13±0.01]mg/L)(P=0.003).PS100-Beta levels did not differ in outpatients with F 0–3 compared to F 4 fibrosis(P=0.670).PS100-Beta values were correlated with Child-Pugh score(P<0.001),Model for End-Stage Liver Disease(MELD)score(P=0.004),C-reactive protein(P<0.001),ammonemia(P<0.001),and chronic liver failure consortium(CLIF-C)organ failure(P<0.001)and CLIF-C acute-on-chronic(P=0.038)scores,but not with leukocytes(P=0.053),procalcitonin(PCT)(P=0.107),or the lymphocyte-to-neutrophil ratio in ICU patients(P=0.522).In a multivariate model including age,ammonemia,PS100-Beta,PCT,MELD,presence of transjugular portosystemic shunt,and sodium level,the diagnostic performance was 0.765 for the diagnosis of overt HE.Patients with a PS100-Beta level<0.12 mg/L had a better overall survival(P=0.019)and a better survival without liver transplantation(P=0.013).Conclusions Serum levels of PS100-Beta are elevated in ICU patients with decompensated cirrhosis,and even more so in those displaying overt HE,and the levels are correlated with outcome.This suggests an increase in the permeability of the BBB in these patients.展开更多
Cutaneous neurogenic inflammation （CNI） is inflammation that is induced （or enhanced） in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular...Cutaneous neurogenic inflammation （CNI） is inflammation that is induced （or enhanced） in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 （TRPV1 and TRPA1, respectively） are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neu- ronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.展开更多
基金supported by the Fondation pour le Recherche Médicale(grant number:EQU202003010517).
文摘Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest altered functioning of the blood–brain barrier(BBB).Assessing BBB function is challenging in clinical practice and at the bedside.Protein-S-100 Beta(PS100-Beta)could be a useful peripheral marker of BBB permeability in HE.This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit(ICU)with decompensated cirrhosis with and without overt HE.Methods We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement.Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded.Overt HE was defined as West-Haven grades 2 to 4.The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes.After ICU discharge,the patients were followed for at least 3 months for the occurrence of overt HE.Adverse outcomes(liver transplantation or death)were collected.The ability of PS100-Beta–in combination with other factors–to predict overt HE was evaluated in a multivariate analysis using logistic regression.Likelihood ratios were used to determine the effects and calculate odds ratios(OR).Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test.Results A total of 194 ICU patients and 207 outpatients were included in the study.Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients([0.15±0.01]mg/L vs.[0.08±0]mg/L,P<0.001).ICU patients with overt HE had higher levels of PS100-Beta([0.19±0.03]mg/L)compared with the ICU patients without overt HE([0.13±0.01]mg/L)(P=0.003).PS100-Beta levels did not differ in outpatients with F 0–3 compared to F 4 fibrosis(P=0.670).PS100-Beta values were correlated with Child-Pugh score(P<0.001),Model for End-Stage Liver Disease(MELD)score(P=0.004),C-reactive protein(P<0.001),ammonemia(P<0.001),and chronic liver failure consortium(CLIF-C)organ failure(P<0.001)and CLIF-C acute-on-chronic(P=0.038)scores,but not with leukocytes(P=0.053),procalcitonin(PCT)(P=0.107),or the lymphocyte-to-neutrophil ratio in ICU patients(P=0.522).In a multivariate model including age,ammonemia,PS100-Beta,PCT,MELD,presence of transjugular portosystemic shunt,and sodium level,the diagnostic performance was 0.765 for the diagnosis of overt HE.Patients with a PS100-Beta level<0.12 mg/L had a better overall survival(P=0.019)and a better survival without liver transplantation(P=0.013).Conclusions Serum levels of PS100-Beta are elevated in ICU patients with decompensated cirrhosis,and even more so in those displaying overt HE,and the levels are correlated with outcome.This suggests an increase in the permeability of the BBB in these patients.
文摘Cutaneous neurogenic inflammation （CNI） is inflammation that is induced （or enhanced） in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 （TRPV1 and TRPA1, respectively） are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neu- ronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.
