- Email: [email protected]
Does Minimal Hepatic Encephalopathy Predict Development of Overt Hepatic Encephalopathy in Children with Chronic Liver Disease?
(P < 0.0001) cytokines in comparison to patients with decompensated cirrhosis without ACLF. Conclusion: Patients with decompensated cirrhosis with and without ACLF have similar impairment in HLA-DR expression and NOB capacity. Both inflammatory and anti-inflammatory cytokines are increased in patients with ACLF in comparison to decompensated cirrhosis without ACLF.
CONFLICTS OF INTEREST The authors have none to declare. Corresponding author: Ajay Duseja. E-mail: [email protected] http://dx.doi.org/10.1016/j.jceh.2017.01.068
66 BRAIN GLYMPHATIC CLEARANCE IS IMPAIRED IN A RAT MODEL OF CIRRHOSIS Anna Hadjihambi, Ian Harrison, Giovanni Rizzo, Jane Macnaughtan, Nigel Beaton, Nathan Davies, Abeba Habtetion, Rajiv Jalan Liver and Digestive health, UCL, London, UK
Background and Aims: The ‘‘glymphatic system’’ is the global waste clearance pathway of the brain, which effectively eliminates metabolites and waste products from the CNS through cerebrospinal (CSF) and interstitial fluid (ISF) exchange. This process depends on the use of the perivascular tunnels, formed by astrocytes and it is mostly active during sleep. Evidence exist indicating altered clearance of the brain during certain pathologies such as Alzheimer's disease and traumatic brain injury. In patients with hepatic encephalopathy (HE) sleep disturbances are reported and changes in the cerebrospinal fluid composition have been identified, such as elevated acetylated compounds, amino acids and bile acids suggesting alterations in metabolic pathways. In this study we investigated whether glymphatic function is affected during HE, by using dynamic contrast-enhanced MRI to quantify glymphatic clearance in the brain of an animal (rat) model of HE (bile duct ligation [BDL]). We also aimed to correlate the effectiveness of this clearance pathway with the concentration of toxic metabolites; bile acids, in the CSF of these animals. Methods: Glymphatic clearance in BDL- (n = 5) and SHAM-operated (n = 5) rats was measured via intracisternal infusion of gadolinium, concurrent with serial acquisition of T1-weighted MR images. In addition, bile acid
concentrations from extracted plasma and CSF were assessed using liquid chromatography–mass spectrometry. Immunofluorescence and PCR was also performed on the brain of these animals to quantify the presence of the most abundant bile acid receptor, TGR5. Results: A dysfunction in the clearance pathway of the brain was observed in the BDL rats compared to sham, with the most affected areas being in the rostral brain, i.e. the olfactory bubs and rostral region of the cortex. The caudal brain (i.e. the caudal region of the cortex, the hippocampus, thalamus and midbrain) of BDL rats however was observed to display an improvement in glymphatics inflow compared to sham controls. Blood and CSF analysis showed a significant increase of the Taurobile acid, which is the main rodent form. An increase in the gene and protein expression of TGR5 was also observed at the caudal brain regions of the BDL rats similar to the regions affected in the MRI experiments. Conclusions: These results show for the first time a brain clearance dysfunction occurring in chronic liver failure, which could be the cause or consequence of the toxic bile acid accumulation. Although the molecular mechanism of this disturbance is unclear, the altered glymphatic pathway in the brain could have many detrimental effects such as sleep disturbances as well as altered mood and consciousness, due to the accumulation of neurotransmitters, toxins and byproducts of cell metabolism. Collectively, this may contribute to the chronic brain injury that is characteristic of patients with cirrhosis and HE.
CONFLICTS OF INTEREST The authors have none to declare. Corresponding author: Anna Hadjihambi. E-mail: [email protected] http://dx.doi.org/10.1016/j.jceh.2017.01.069
67 DOES MINIMAL HEPATIC ENCEPHALOPATHY PREDICT DEVELOPMENT OF OVERT HEPATIC ENCEPHALOPATHY IN CHILDREN WITH CHRONIC LIVER DISEASE? Anshu Srivastava, Saurabh Chaturvedi, Surender Kumar Yachha, Rakesh Kumar Gupta, Chandra M. Pandey Department of Biostatistics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
Journal of Clinical and Experimental Hepatology | February 2017 | Vol. 7 | No. S1 | S22–S83
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POSTER PRESENTATION
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
POSTERS
POSTER PRESENTATION
Introduction and aim: Minimal hepatic encephalopathy (MHE) predicts development of overt hepatic encephalopathy (OHE) in adults with chronic liver disease (CLD) 1. However, there is scarce data on MHE in children with CLD and no information regarding its role in the prediction of OHE. The aim was to evaluate if CLD children with MHE are at a higher risk of developing OHE than those without MHE. Patients and methods: 67 children (38 boys, age 13 [7– 18] y) with CLD and no past history of OHE were evaluated for MHE by neuropsychological testing as part of another prospective study and 34 (50.7%) of them were found to have MHE. 58 of these cases (29 each with MHE and NoMHE) were in follow-up and they were evaluated for development of OHE. The factors associated with development of OHE in follow-up were analyzed by univariate and multivariate analysis. Results: 7/58 (12%) children with CLD developed OHE over a follow-up period of 25 (1–54) months; 3 of them died and 4survived. The age (192 [120–204] vs. 156 [84– 216] months; p = 0.07), weight Z score (1.2 [2.1 to 0.6] vs. 1.07 [2.5 to 2.5]; P = 0.9) and height Z score (0.53 [2.3 to 0.8] vs. 1.6 [4.1 to 1.5]; P = 0.4), was similar in the patients with OHE (n-7) and No-OHE (n-51). Patients with OHE had higher bilirubin (7.4 [2.4–29] vs. 1.7 [0.5– 23.9] mg/dl; P = 0.01) and lower albumin (2.8 [2.4–3.2] vs. 3.5 [1.5–4.2] g/dL; P = 0.01) and haemoglobin (10.5 [7.8– 10.8] vs. 10.9 [5–13.9] g/dL; P = 0.02) than those with NoOHE. International normalized ratio (INR) was higher in the OHE group (1.7 [1.4–2.7] vs. 1.4 [1–2.6]; P = 0.1) but not significantly. The Child Pugh (n = 58, 10 [8–12] vs. 7 [5–12]; P = 0.005), MELD (n = 39, 20 [16–27] vs. 13 [7–32]; P = 0.02) and PELD score (n = 19, 21 vs. 11 [1–21]; P = 0.4) was higher in patients with OHE in comparison to those without OHE. Development of OHE was equally common in patients with MHE and No-MHE (3/29 vs. 4/29; P = 1.0) but it developed earlier in the MHE patients (3 [1–6] vs. 11.5 [6–30] months; P = 0.1). Patients who received specific etiology based therapy had a lower risk of OHE than those who did not (4/39 vs. 3/19; P = 0.6), though not significant. Child Pugh score was the only significant factor predicting OHE on multivariate analysis. Conclusion: 12% children with CLD developed OHE over a median follow-up of 25 months. The development of OHE was similar in children with and without MHE. Higher Child Pugh score independently predicted development of OHE [1]. Disclosures: This study is an extension of a prospective study for diagnosis of MHE in children with CLD which was sponsored by the Indian Council of Medical Research, N Delhi. The main study on prevalence and diagnostic modalities for MHE in children has been accepted.
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CONFLICTS OF INTEREST The authors have none to declare.
REFERENCE [1]. Ampere J, Simon M, Mongolia C, et al. Minimal Hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis. Gastroenterology. 2015;149:1483–1489.
Corresponding author: Anshu Srivastava. E-mail: [email protected] http://dx.doi.org/10.1016/j.jceh.2017.01.070
68 STATISTICAL MULTI-STATE MODELLING OF PROGRESSION FROM ACUTE LIVER FAILURE TO INTRACRANIAL HYPERTENSION AND DEATH Peter Nissen Bjerring, Fin Stolze Larsen Department of Hepatology, Rigshospitalet, Copenhagen, Denmark
Background and Aims: The clinical course of patients with acute liver failure (ALF) is associated with a high risk of intracranial hypertension and death. Efforts to investigate risk factors for developing intracranial hypertension (ICH) are challenged by the competing risk situation given by the high mortality. In this study we aim to identify risk factors of development of intracranial hypertension in a cohort of high-risk ALF patients by the use of multi-state modelling. Patients and methods: 44 patients (26 females) with ALF and persistent hyperammonaemia (>150 mM for 24 h) or clinical signs of ICH were included over a ten year period. Cerebral microdialysis and monitoring of intracranial pressure (ICP) was initiated while the patients were mechanically ventilated and sedated. Baseline values of ICP, arterial lactate and ammonia were measured upon inclusion. Furthermore the need for renal replacement therapy and/or vasopressors was registered. The concentration of lactate, pyruvate and glutamine was measured in the microdialysate. ICH was defined as ICP > 20 mmHg for more than one hour. Time (hours) to ICH and/or death measured from initiation of ICP-monitoring was registered. A multi-state model was fitted and covariates with discriminative power (P > 0.15) in univariate analysis were included as binary predictors. Results: A four-state model (ALF, ICH, liver transplantation (LTX) or death) was fitted and state occupation probabilities for the first seven days are given in Figure 1. © 2017, INASL
CONFLICTS OF INTEREST The authors have none to declare. Corresponding author: Ajay Duseja. E-mail: [email protected] http://dx.doi.org/10.1016/j.jceh.2017.01.068
66 BRAIN GLYMPHATIC CLEARANCE IS IMPAIRED IN A RAT MODEL OF CIRRHOSIS Anna Hadjihambi, Ian Harrison, Giovanni Rizzo, Jane Macnaughtan, Nigel Beaton, Nathan Davies, Abeba Habtetion, Rajiv Jalan Liver and Digestive health, UCL, London, UK
Background and Aims: The ‘‘glymphatic system’’ is the global waste clearance pathway of the brain, which effectively eliminates metabolites and waste products from the CNS through cerebrospinal (CSF) and interstitial fluid (ISF) exchange. This process depends on the use of the perivascular tunnels, formed by astrocytes and it is mostly active during sleep. Evidence exist indicating altered clearance of the brain during certain pathologies such as Alzheimer's disease and traumatic brain injury. In patients with hepatic encephalopathy (HE) sleep disturbances are reported and changes in the cerebrospinal fluid composition have been identified, such as elevated acetylated compounds, amino acids and bile acids suggesting alterations in metabolic pathways. In this study we investigated whether glymphatic function is affected during HE, by using dynamic contrast-enhanced MRI to quantify glymphatic clearance in the brain of an animal (rat) model of HE (bile duct ligation [BDL]). We also aimed to correlate the effectiveness of this clearance pathway with the concentration of toxic metabolites; bile acids, in the CSF of these animals. Methods: Glymphatic clearance in BDL- (n = 5) and SHAM-operated (n = 5) rats was measured via intracisternal infusion of gadolinium, concurrent with serial acquisition of T1-weighted MR images. In addition, bile acid
concentrations from extracted plasma and CSF were assessed using liquid chromatography–mass spectrometry. Immunofluorescence and PCR was also performed on the brain of these animals to quantify the presence of the most abundant bile acid receptor, TGR5. Results: A dysfunction in the clearance pathway of the brain was observed in the BDL rats compared to sham, with the most affected areas being in the rostral brain, i.e. the olfactory bubs and rostral region of the cortex. The caudal brain (i.e. the caudal region of the cortex, the hippocampus, thalamus and midbrain) of BDL rats however was observed to display an improvement in glymphatics inflow compared to sham controls. Blood and CSF analysis showed a significant increase of the Taurobile acid, which is the main rodent form. An increase in the gene and protein expression of TGR5 was also observed at the caudal brain regions of the BDL rats similar to the regions affected in the MRI experiments. Conclusions: These results show for the first time a brain clearance dysfunction occurring in chronic liver failure, which could be the cause or consequence of the toxic bile acid accumulation. Although the molecular mechanism of this disturbance is unclear, the altered glymphatic pathway in the brain could have many detrimental effects such as sleep disturbances as well as altered mood and consciousness, due to the accumulation of neurotransmitters, toxins and byproducts of cell metabolism. Collectively, this may contribute to the chronic brain injury that is characteristic of patients with cirrhosis and HE.
CONFLICTS OF INTEREST The authors have none to declare. Corresponding author: Anna Hadjihambi. E-mail: [email protected] http://dx.doi.org/10.1016/j.jceh.2017.01.069
67 DOES MINIMAL HEPATIC ENCEPHALOPATHY PREDICT DEVELOPMENT OF OVERT HEPATIC ENCEPHALOPATHY IN CHILDREN WITH CHRONIC LIVER DISEASE? Anshu Srivastava, Saurabh Chaturvedi, Surender Kumar Yachha, Rakesh Kumar Gupta, Chandra M. Pandey Department of Biostatistics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
Journal of Clinical and Experimental Hepatology | February 2017 | Vol. 7 | No. S1 | S22–S83
S53
POSTER PRESENTATION
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
POSTERS
POSTER PRESENTATION
Introduction and aim: Minimal hepatic encephalopathy (MHE) predicts development of overt hepatic encephalopathy (OHE) in adults with chronic liver disease (CLD) 1. However, there is scarce data on MHE in children with CLD and no information regarding its role in the prediction of OHE. The aim was to evaluate if CLD children with MHE are at a higher risk of developing OHE than those without MHE. Patients and methods: 67 children (38 boys, age 13 [7– 18] y) with CLD and no past history of OHE were evaluated for MHE by neuropsychological testing as part of another prospective study and 34 (50.7%) of them were found to have MHE. 58 of these cases (29 each with MHE and NoMHE) were in follow-up and they were evaluated for development of OHE. The factors associated with development of OHE in follow-up were analyzed by univariate and multivariate analysis. Results: 7/58 (12%) children with CLD developed OHE over a follow-up period of 25 (1–54) months; 3 of them died and 4survived. The age (192 [120–204] vs. 156 [84– 216] months; p = 0.07), weight Z score (1.2 [2.1 to 0.6] vs. 1.07 [2.5 to 2.5]; P = 0.9) and height Z score (0.53 [2.3 to 0.8] vs. 1.6 [4.1 to 1.5]; P = 0.4), was similar in the patients with OHE (n-7) and No-OHE (n-51). Patients with OHE had higher bilirubin (7.4 [2.4–29] vs. 1.7 [0.5– 23.9] mg/dl; P = 0.01) and lower albumin (2.8 [2.4–3.2] vs. 3.5 [1.5–4.2] g/dL; P = 0.01) and haemoglobin (10.5 [7.8– 10.8] vs. 10.9 [5–13.9] g/dL; P = 0.02) than those with NoOHE. International normalized ratio (INR) was higher in the OHE group (1.7 [1.4–2.7] vs. 1.4 [1–2.6]; P = 0.1) but not significantly. The Child Pugh (n = 58, 10 [8–12] vs. 7 [5–12]; P = 0.005), MELD (n = 39, 20 [16–27] vs. 13 [7–32]; P = 0.02) and PELD score (n = 19, 21 vs. 11 [1–21]; P = 0.4) was higher in patients with OHE in comparison to those without OHE. Development of OHE was equally common in patients with MHE and No-MHE (3/29 vs. 4/29; P = 1.0) but it developed earlier in the MHE patients (3 [1–6] vs. 11.5 [6–30] months; P = 0.1). Patients who received specific etiology based therapy had a lower risk of OHE than those who did not (4/39 vs. 3/19; P = 0.6), though not significant. Child Pugh score was the only significant factor predicting OHE on multivariate analysis. Conclusion: 12% children with CLD developed OHE over a median follow-up of 25 months. The development of OHE was similar in children with and without MHE. Higher Child Pugh score independently predicted development of OHE [1]. Disclosures: This study is an extension of a prospective study for diagnosis of MHE in children with CLD which was sponsored by the Indian Council of Medical Research, N Delhi. The main study on prevalence and diagnostic modalities for MHE in children has been accepted.
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CONFLICTS OF INTEREST The authors have none to declare.
REFERENCE [1]. Ampere J, Simon M, Mongolia C, et al. Minimal Hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis. Gastroenterology. 2015;149:1483–1489.
Corresponding author: Anshu Srivastava. E-mail: [email protected] http://dx.doi.org/10.1016/j.jceh.2017.01.070
68 STATISTICAL MULTI-STATE MODELLING OF PROGRESSION FROM ACUTE LIVER FAILURE TO INTRACRANIAL HYPERTENSION AND DEATH Peter Nissen Bjerring, Fin Stolze Larsen Department of Hepatology, Rigshospitalet, Copenhagen, Denmark
Background and Aims: The clinical course of patients with acute liver failure (ALF) is associated with a high risk of intracranial hypertension and death. Efforts to investigate risk factors for developing intracranial hypertension (ICH) are challenged by the competing risk situation given by the high mortality. In this study we aim to identify risk factors of development of intracranial hypertension in a cohort of high-risk ALF patients by the use of multi-state modelling. Patients and methods: 44 patients (26 females) with ALF and persistent hyperammonaemia (>150 mM for 24 h) or clinical signs of ICH were included over a ten year period. Cerebral microdialysis and monitoring of intracranial pressure (ICP) was initiated while the patients were mechanically ventilated and sedated. Baseline values of ICP, arterial lactate and ammonia were measured upon inclusion. Furthermore the need for renal replacement therapy and/or vasopressors was registered. The concentration of lactate, pyruvate and glutamine was measured in the microdialysate. ICH was defined as ICP > 20 mmHg for more than one hour. Time (hours) to ICH and/or death measured from initiation of ICP-monitoring was registered. A multi-state model was fitted and covariates with discriminative power (P > 0.15) in univariate analysis were included as binary predictors. Results: A four-state model (ALF, ICH, liver transplantation (LTX) or death) was fitted and state occupation probabilities for the first seven days are given in Figure 1. © 2017, INASL