W. Bernal

Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis

BACKGROUND & AIMS Patients with cirrhosis are prone to infection which is a frequent precipitant of hepatic encephalopathy (HE). Clinical studies have examined the importance of inflammation and infection in modulating the manifestation of symptoms of HE in acute liver failure and patients with cirrhosis and minimal/low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis although this has not been examined to date. METHODS We report the findings of a prospective audit of 100 consecutive patients with cirrhosis admitted between Jan 2000 and March 2008 to a liver Intensive Care Unit (ICU) where HE was the primary indication for admission (59% Grade 3; 41% Grade 4). Haematological and microbiological data were collected at ICU admission, and organ scores and outcomes were recorded. RESULTS 46% of patients had positive cultures taken within ± 48h from admission to ICU [25% blood] and a further 22% were culture negative but had evidence of systemic inflammation (SIRS). SIRS score (p=0.03) and SOFA score (p=0.006) were significantly higher in those patients with Grade 4 HE, who were also less likely to survive (p<0.001). HE grade/coma score did not correlate with ammonia, biochemistry or MELD score. Fifty-two percent of patients survived their ICU stay while the remainder developed progressive multiorgan failure and died; 38% survived to discharge, and 16% were transplanted. CONCLUSIONS These data support an association between infection/SIRS and not ammonia, in patients with cirrhosis that develop severe HE. The presence or absence of infection/SIRS did not determine survival.

Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long-term outcome and survival

Background  Primary sclerosing cholangitis/autoimmune hepatitis (PSC/AIH) and primary biliary cirrhosis/AIH (PBC/AIH) overlap syndromes are poorly defined variants of AIH. Few large patient series exist, and there are little data on long‐term outcomes.

A community prevalence study of antibodies to hepatitis A and E in inner-city London

The seroprevalence of antibodies to hepatitis E virus (HEV) and hepatitis A virus (HAV) was determined in a community‐based sample in inner‐city London where socioeconomic conditions were expected to result in a high prevalence of antibodies to HAV, and in which the presence of immigrants from the developing world pose a risk of imported infection of both HAV and HEV. The seroprevalence of anti‐HAV was 45.1% in UK born subjects and 69.7% in non‐UK born subjects and each group showed differing patterns of age‐specific seroprevalence. The seroprevalence rates of anti‐HEV was 3.9% in UK born subjects and 8.8% in non‐UK born subjects. The age‐specific seroprevalence of the UK born group is suggestive of a cohort effect. The data suggest a low circulation of HEV in inner‐city London, remaining uncommon relative to HAV.

The interleukin-1 and interleukin-10 gene polymorphisms in primary sclerosing cholangitis: no associations with disease susceptibility/resistance

BACKGROUND/AIMS Although primary sclerosing cholangitis is believed to be an autoimmune disorder, no tissue-specific auto-antibodies have yet been identified, and the strongest support for an autoimmune aetiology comes from HLA-association studies. Three different HLA haplotypes are associated with susceptibility to the disease and one with protection from it. These HLA haplotypes, however, do not account for all of the disease risk and genes outside the HLA region may also have a role in disease pathogenesis. The aim of this study was to investigate, for the first time, polymorphic genes/sites within the interleukin-1 and interleukin-10 genes in a large well-characterised group of patients. METHODS Ninety-six patients and 96 control subjects were studied. A single base-exchange polymorphism at position +3953 in the first exon of the IL-1B gene, a penta-allelic repeat sequence in the IL-1 receptor antagonist gene (IL-1RN) and three single base-exchange polymorphisms at positions -592, -819 and -1082 in the IL-10 gene promoter were determined by standard PCR-based techniques. RESULTS Overall, there was no significant difference in the distribution of any of the IL-1B, IL-1RN or IL-10 alleles or genes sequences comparing patients and controls. In addition, there was no difference when the patients were stratified for the presence and absence of the HLA DRB1*0301 (DR3) allele or concurrent inflammatory bowel disease. CONCLUSION Neither the IL-1B +3953, IL-1RN microsatellites polymorphisms on chromosome 2q13 nor the IL-10 -592, -819, -1082 promoter gene polymorphisms on chromosome 1q31-32 are associated with susceptibility or resistance to primary sclerosing cholangitis.

56 THE PROPHYLACTIVE EFFECT OF MILD HYPOTHERMIA TO PREVENT BRAIN EDEMA IN PATIENTS WITH ACUTE LIVER FAILURE: RESULTS OF A MULTICENTER RANDOMIZED, CONTROLLED TRIAL

56 THE PROPHYLACTIVE EFFECT OF MILD HYPOTHERMIA TO PREVENT BRAIN EDEMA IN PATIENTS WITH ACUTE LIVER FAILURE: RESULTS OF A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL F.S. Larsen, N. Murphy, W. Bernal, P.N. Bjerring, J. Hauerberg, J. Wendon, EUROALF Group. Hepatology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; Intensive Care, Queen Elizabeth Hospital, Birmingham, Institute of Liver Studies, London, UK; Neurosurgy, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; Institute of Liver Studies, Kings College Hospital, London, UK E-mail: stolze@post3.tele.dk

Comparison of scoring systems and outcome of patients admitted to a liver intensive care unit of a tertiary referral centre with severe variceal bleeding

Acute variceal haemorrhage (AVH) is associated with significant mortality.

External validation of the USALFSG acute liver failure outcome prediction criteria

Citing this paper Please note that where the full-text provided on Kings Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publishers definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publishers website for any subsequent corrections.

629 CEREBRAL OEDEMA IS RARE IN ACUTE-ON-CHRONIC LIVER FAILURE (AOCLF)

mediated immune response. These immune modulations, and the peripheral T-cell depletion known to occur in cirrhosis, may support development of autoimmunity. We therefore aimed to investigate whether cirrhosis confers an increased risk of autoimmune disease. Methods: We used the Danish National Patient Registry (NPR) to identify all Danish citizens diagnosed with cirrhosis in 1977– 2009. For each of them we sampled five genderand age-matched population controls. Cox regression was used to compare the rate of rheumatoid arthritis, multiple sclerosis, or inflammatory bowel disease development (identified through NPR) between cirrhosis patients and controls. Results: We included 38,394 cirrhotic patients. During 217,558 total years of follow-up 442 of them developed rheumatoid arthritis (N =206), multiple sclerosis (N=20), or inflammatory bowel disease (N=216). Cirrhosis patients were more likely than controls to develop autoimmune disease (hazard ratio 1.66, 95%CI 1.49–1.85), irrespective of gender. The association was strongest shortly after cirrhosis was diagnosed and stable at a hazard ratio of about 1.45 from two years on after diagnosis of cirrhosis. Conclusion: Liver cirrhosis associates with development of multiple sclerosis, inflammatory bowel disease and/or rheumatoid arthritis. This may indicate a general enhancement in susceptibility for autoimmune phenomena in cirrhosis, and the underlying mechanisms should be delineated.

P02 Apoptosis in paracetamol-induced acute liver failure: importance of extra-hepatic organ dysfunction

Introduction Both necrotic and apoptotic hepatocyte death pathways have been implicated in paracetamol induced ALF (PALF). Elevated circulating levels of M30, a marker of caspase-3 activation, have been demonstrated in this condition and are postulated to reflect hepatocellular apoptosis. This novel marker has also been reported to have clinical utility as a prognostic indicator in ALF. However, published results are conflicting and it remains unclear whether significant hepatocyte apoptosis is clinically relevant in PALF. Aim To investigate the role of hepatocyte apoptosis in PALF. Method Serum M30 levels were quantified by ELISA (Peviva, Bromma, Sweden) in 62 patients with PALF (34 spontaneous survivors (S) and 28 OLT or died (D)). Control groups of 10 healthy volunteers and 20 chronic HCV patients were used for comparison. Clinical outcome measures in PALF were correlated with M30 levels. In four patients undergoing transplantation for PALF, blood was sampled from the hepatic vein (HV), portal vein (PV) and a systemic artery and serum levels of M30 quantified as above. A focused proteome apoptosis array was performed on liver homogenates from 4 PALF cases and 4 controls. Protein was quantified using a modified Lowry assay and concentrations normalised. Array films were scanned and analysed in ImageJ. H&E stained liver sections from AALF patients were examined for histological evidence of apoptosis. Results Serum M30 levels were significantly elevated in PALF (3970 IU/l) compared with both healthy volunteers (144 IU/l) and HCV patients (170 IU/l) (p<0.001). Serum levels of M30 were significantly elevated in PALF-D compared to PALF-S (5199 vs 2357 IU/l; p<0.0005). There was a transportal gradient of M30 in all patients tested, with highest levels in the PV and lowest in the HV (p<0.03). Systemic arterial M30 levels were intermediate between the PV and HV levels (Abstract P02 figure 1). Analysis of apoptosis arrays showed significant downregulation of a number of apoptosis-associated proteins, including Bax, HIF-1, FADD and SMAC/Diablo (p<0.04) (Abstract P02 figure 2). Catalase was markedly elevated compared to controls in three of the four AALF patients. Histological evaluation revealed confluent hepatocellular loss, epithelial regenerative activity and an absence of apoptotic bodies.Abstract P02 Figure 1 Regional levels of M30 (marker of cleaved cytokeratin-18) in four cases of Paracetamol-induced acute liver failure.Abstract P02 Figure 2 Downregulation of apoptosis-associated proteins in AALF patients (n=4) compared with controls (n=4). Conclusion In this large cohort of PALF patients we have demonstrated the presence of elevated M30 levels and a correlation between caspase three activation and poor clinical outcome. The transhepatic M30 gradient, down regulation of apoptosis-associated proteins and histological appearances indicate that hepatocellular apoptosis might not be the major source of circulating M30. Our data also indicate that in established PALF, apoptosis in non-hepatic epithelial tissues may predominate and is likely to reflect incipient multi-organ failure, with resulting poor outcomes.Abstract P02 Figure 3 Examples of apoptosis array for case and control.

P138 SERONEGATIVE ACUTE LIVER FAILURE REPRESENTS A MACROPHAGE–T CELL ACTIVATION SYNDROME

P136 DEFICIENCY OF IL-33 SENSITIZES TO SEVERE LIVER INJURY INDUCED BY ConA BUT NOT BY CCl4 IN MICE M.I. Arshad, A. Filliol, V. Genet, C. Lucas-Clerc, J.-P. Girard, C. Piquet-Pellorce, M. Samson. Inserm U 1085, Institut de Recherche Sante Environnement & Travail (IRSET), Rennes, France; Institute of Microbiology, University of Agriculture, Faisalabad, Pakistan; Service de Biochimie CHU Rennes, Universite de Rennes 1, Rennes, Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique (IPBS-CNRS), Universite de Toulouse, Toulouse, Structure Federative BioSit UMS 3480 CNRS-US 18 Inserm, Rennes, France E-mail: michel.samson@univ-rennes1.fr