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Methods: Reference hepatologists were identified in Argentina, Uruguay, Chile, Brazil, Mexico, Peru, Venezuela and Bolivia, who in turn were commissioned to establish national specialist networks contributing to the project. Data would be obtained using the methodology in place at the Spanish DILI Registry. Identified cases would be remitted to the coordinating centre in Malaga for causality assessment and information storage. Results: Seventy-three DILI cases have been analyzed up to November 2012, having a mean age of 52 years (range 15–86) and female predominance (60%). The therapeutic groups most frequently implicated were NSAIDs (22%) including nimesulide (5 cases) and diclofenac (4 cases); antiinfectives (19%) including nitrofurantoin (3 cases), herbal remedies (12%) including Morinda citrifolia, Peumus boldus and Monascus purpureus; hormonal therapy (12%) including cyproterone acetate (4 cases); and central nervous system drugs (11%). Hepatocellular injury (50%) was the most common type of liver damage. Jaundice was seen in 71% of cases, 53% required hospitalization and 38% fulfilled Hy’s Law criteria (66% of hormonal therapy cases, 44% of herbal cases). Positive autoantibody titers were present in 29% of cases, mainly antinuclear. Six cases were autoimmune hepatitis DILI (8%) and five cases had experienced a second DILI episode (7%). Conclusions: This initial analysis demonstrates similar phenotypic characteristics as observed in registers outside Latin America with respect to type of injury and severity. However, female cases seem to predominate in Latin America. With regards to causative agents, elevated representation of NSAIDs, hormonal treatments and herbal remedies were evidenced. Funding: Agencia Espanola del Medicamento. Proyecto Excelencia SAS P10CTS-6470. iSAEC. CIBERehd is funded by ISCIII.

57 SECRETORY LEUKOCYTE PROTEASE INHIBITOR (SLPI) IS A PIVOTAL MEDIATOR OF ANTI-INFLAMMATORY RESPONSES IN ACUTE LIVER FAILURE C. Antoniades, W. Khamri, R. Abeles, A. O’Brien, L. Possamai, W. Bernal, C. Starling, R. Mitry, G. Auzinger, D. Gilroy, M. Heneghan, N. Heaton, A. Quaglia, D. Vergani, J. Wendon, M. Thursz. Section of Hepatology, Imperial College London, Intitute of Liver Sciences, King’s College London, Metabolism & Experimental Therapeutics, Faculty of Medical Sciences, UCL, London, UK E-mail: c.antoniades@imperial.ac.uk

Two cases of neonatal haemochromatosis, a rare and often fatal metabolic disorder, presenting with acute liver failure, are reported. Both presented in the first week of life with hypoglycaemia, jaundice, and coagulopathy, with rapid deterioration of liver function. Both received a transplantation using reduced liver grafts. One child was well 18 months later. Few survivors have been reported and despite the difficult perioperative management, liver transplantation is the best treatment for neonatal haemochromatosis.

Introduction Hepatocellular carcinoma (HCC) is a major cause cancer-related mortality, world wide. In particular, HCC is associated with chronic hepatitis B infection (CHB) in Africa and South East Asia. Most published data relating to the natural history of CHB and HCC originates from South East Asia; however due to differences in HBV genotype and potential environmental and genetic factors, it is not clear whether this data are applicable to the African population. Therefore, to explore this issue we have compared the characteristics and outcomes of patients with CHB and HCC according to ethnic origin. Methods Patients with HCC complicating CHB, managed at King9s College Hospital London, were identified from our clinic databases. Demographic information, laboratory parameters, initial tumour staging and outcome data, including HBe-antigen status, viral load and genotype, were collated where available. Comparison was performed between Black patients and patients of South East Asian origin. Results In total, 295 patients with HCC and CHB were identified. Median age at the diagnosis of tumour was 37 years and 85% of patients were male. Ethnicity was classified as Black in 27% of patients and South East Asian in 21% of these patients. Cirrhosis was present in 81% whereas 8% were non-cirrhotic at diagnosis of HCC; data were unavailable in the remaining 11% of patients. 18% were HBe-antigen positive and 7% hepatitis C antibody positive. The distribution of HBV genotypes varied according to ethnic group, with genotypes A and E restricted to Black patients and genotypes B and C to South East Asian patients. On comparing these two groups, there were no differences in gender, the presence of cirrhosis, co-factors for liver disease, laboratory parameters or tumour stage, as assessed by the BCLC staging system. However, Black patients were significantly younger (median age: 44 vs 61 years, p Conclusion In our cohort, we have observed that Black patients present at a younger age and have poorer length of survival in comparison to South East Asian patients. This may represent a more aggressive HCC phenotype that is associated with HBV genotypes A and E although there are potentially multiple confounding factors. Further research is required to determine the cause of this apparent inequality. Competing interests None declared.

Introduction The presence of comorbidities negatively impact post liver transplant (LT) survival for those transplanted with chronic liver disease. Methods assess the impact of comorbidities on survival in patients transplanted for acute liver failure (ALF). Results 176 patients underwent LT for ALF over 9 years. Median follow-up was 92 months (range 35–142). Median age was 33 years (17–67) and 122 (69.3%) were females. Fifty-nine patients (33.5%) were transplanted for Paracetamol induced ALF. Ninety-six (54.6%) patients had ≥1 comorbidity. The commonest comorbidity was renal dysfunction in 84 (48%), pulmonary disease in 10 (6%), connective tissue disease in 5 (3%) and 2 (1%) had diabetes. Patients with ≥1 comorbidity had significantly increased 6 month (25% vs 13%, p=0.046), 12 month (27% vs 13%, p=0.023) and overall mortality (32% vs 17%, p=0.019). Similar results were demonstrated for graft survival. Recipient age ≥ 40 years (OR=1.37, 95% CI 1.02 to 1.86, p=0.039), the presence of comorbidity (OR=1.46, 95% CI 1.05 to 2.03, p=0.022) and renal dysfunction (OR=1.62, 95% CI 1.18 to 2.23, p=0.003) were associated with increased post LT mortality on univariate analysis. However, only the presence of comorbidity (OR=1.43, 95% CI 1.03 to 1.98, p=0.032) and renal dysfunction (OR=1.59, 95% CI 1.15 to 2.19, p=0.004) were independently associated with mortality. Other recipient related, donor, or graft variables were not associated with mortality. Patients with ≥1 comorbidity had significantly increased ICU length of stay (LoS) of 20 days (3 to 134) compared to those without comorbidities, 16 days (2–102), p=0.005. Conclusion Pre- LT comorbidity as defined by the presence of ≥1 comorbidity, significantly impairs overall post-LT patient and graft survival in patients transplanted for ALF. Patients with ≥1 comorbidity had significantly increased ICU LoS which may suggest increased resource utilisation. Competing interests None declared. Reference 1. Volk ML , et al . Modified Charlson comorbidity Index for predicting survival after liver transplantation. Liver Transplant 2007; 13 :1515–20.

Introduction In selected patients, liver transplantation (LT) is considered a curative treatment for hepatocellular carcinoma (HCC). With the application of strict eligibility criteria the risk of tumour recurrence can be minimised but never entirely eliminated. Historically, HCC recurrence is associated with a poor prognosis; however the new and evolving systemic therapies may improve outcomes. Hence, there may be a potential beneficial role for early diagnosis. Although, serum alpha-fetoprotein (AFP) measurement is commonly employed in HCC surveillance in at-risk patients, its role following LT for HCC is not clearly defined. Therefore, we have explored (1) the utility of AFP as a biomarker for tumour recurrence following LT in patients with HCC and (2) the influence of liver disease aetiology on its diagnostic performance. Methods The clinical characteristics, laboratory parameters and outcomes of 302 patients with HCC who underwent LT between January 1999 and July 2011 at our institution were reviewed. Serum AFP levels following LT were analysed and the area under a receiver-operator characteristic curve (AUC) calculated to assess the performance of AFP as a diagnostic test for HCC recurrence. Results Recurrent HCC was observed in 13% of patients during the follow-up period. Recurrence was associated with higher pre-LT AFP (98 ng/ml vs 11.5 ng/ml, p>0.001), vascular invasion in the liver explant, and greater tumour size. Following LT, the median time from initial rise in serum AFP to the diagnosis of recurrence was 16 weeks. In our cohort, AFP was an effective predictor of HCC recurrence (AUC 0.843) and using a cut-off value of ≥10 ng/ml was an excellent exclusion test (negative predictive value 0.94). Furthermore, its performance was superior in patients with AFP-secreting tumours at LT, in comparison to those with non-secreting tumours (AUC 0.892 vs 0.710). Patients with chronic hepatitis C (CHC), in comparison to non-infected patients, were younger (56 years vs 60 years, p=0.887) and had a lower MELD score (13 vs 10 ng/ml, p=0.002) but higher serum AFP (21 ng/ml vs 10 ng/ml) at LT. However, there was no difference in recurrence rates between groups. In patients with CHC, AFP was an inferior predictor of HCC recurrence, in comparison non-CHC patients (AUC 0.769 vs 0.887). Conclusion We, therefore, conclude that serum AFP measurement is a potentially useful surveillance investigation for tumour recurrence post-LT for HCC particularly in patients without CHC. Competing interests None declared.

Introduction During normal liver wound-healing, tissue injury causes inflammation and cell death, which in turn orchestrates compensatory cell proliferation and regeneration. 1 If resolution of the injury cannot be obtained the resulting unchecked healing process can lead to cancer. Similar injury-induced repair mechanisms occur in response to chemotherapeutic treatments. 1 We recently found that the use of pre-transplantation TACE for HCC promotes the development of a mixed cholangiocellular phenotype that is associated with the expression of CD133, a marker of hepatic progenitor cells (HPC). This phenomenon is associated with higher post-transplantation tumour recurrence. 2 The molecular bases for the development of the cholangiocellular phenotype have not been investigated before. In this study we identified key oncogenic effectors involved with a “switch” from HCC to cholangiocellular phenotype resulting from liver injury induced by TACE treatment. Methods Ten cases of post-TACE (doxorubicin/lipiodol) treated HCC examined after transplantation at King9s College Hospital were selected for the study. HCC patients not treated by TACE before transplantation were used as control group. Formalin-fixed section from main tumour mass embedded in paraffin blocks were used to perform immunohistochemistry in order to delineate which component of the MAPK signalling pathway is associated with the hepatocholangiocellular phenotype and expression of HPC markers (CD133 and CK19). Results Among the post-TACE liver explants, approximately 50% of the neoplastic cells resembling bile ductules (cholangiocellular differentiation) showed nuclear expression of a specific phospho-activated component of the MAPK cascade. Furthermore, half of the cells positive for activated-MAPK showed proliferative activity, as determined by Ki67 staining. Expression of activated-MAPK was not detected in the non-TACE treated group of liver transplant. Conclusion The development of the mixed hepato-cholangiocellular phenotype in HCC patients after TACE-inflicted liver injury relates to activation of a specific MAPK signalling pathway that promotes proliferation of HPC. Attenuation of this signalling pathway could be used to prevent the “ uncontrolled” proliferation and differentiation of progenitor cells before liver transplantation in HCC patients, and thus improving the tumour recurrence rate. Competing interests None declared. References 1. Papa S , et al. Biol Chem 2009; 390 :965–76. 2. Zen C , et al. Liver Transpl 2011; 17 :943–54.

Introduction Hepatitis C virus (HCV) recurrence post liver transplant (LT) is universal. Sustained virological response (SVR) rates post LT with pegylated interferon (PEG-IFN) and ribavirin (RIB) range between 26% and 50% and are associated with significant side effects. Single nucleotide polymorphisms (SNPs) rs12979860 near the IL28B gene predict response to treatment. Strong immune T helper type 1 responses towards HCV determine also play an integral role in the outcome of infection. Interferon γ inducible protein 10 (IP-10) has been shown to correlate with treatment response in HCV mono-infection and HIV co-infected patients but limited data are available for patients in the post LT period. Our aim was to investigate whether SNPs near IL28B gene rs12979860 and pre-treatment plasma levels of IP-10 can predict treatment response in patients with recurrent HCV post LT. Methods Pre-treatment plasma samples were studied in HCV patients post LT. Plasma levels of IP-10 (pg/ml) was measured by ELISA. rs12979860 were tested by direct sequencing. All patients were treated with PEG-IFN α 2a and weight based RIB for a minimum of 48 weeks irrespective of genotype. Virological response was divided into SVR, null-response (NR) and responder relapse (RR). All results are presented as medians (range). Results 41 patients (34 male) with recurrent HCV (49% genotype one disease) were treated at a median time of 43 months (3–133) post LT. 71% of patients were maintained on tacrolimus monotherapy. Nine patients had been treated previously with PEG-IFN and RIB. Median baseline HCV viral load was 2.35E6 IU/ml. 78% of patients were commenced on a low accelerated dosage regimen (median dose PEG 135 μg, median dose RIB 800 mg). Rs12979860 haplotype CC was present in 24% (8×SVR, 2×RR), CT 59% (10×SVR, 9×NR, 5×RR) and TT in 17% (1×SVR, 6×NR). SVR was achieved by 19 patients (46%), 15 patients were NR (37%) and 7 were RR (17%). Baseline IP-10 levels correlated with serum AST (r=0.48, p=0.003), ALT (r=0.36, p=0.05), fibrosis score (r=0.33, p=0.04) and necro-inflammatory score (r=0.54, p=0.001). IP-10 levels were lower in those who achieved a SVR (116 vs 490, p Conclusion Our data demonstrates that patients with a lower baseline IP-10 level are more likely to achieve a SVR. The IL28B CC haplotype in conjunction with a low IP-10 level predicts treatment success in recurrent HCV post LT. Competing interests None declared.

by APAP (45±3.2) was attenuated following TLR4 antagonist (20±2.3) (p < 0.01). This was associated with a reduction in brain water (p < 0.01). Both the TLR4 antagonists significantly reduced pericentral necrosis of the liver. Both these interventions showed an improvement in the survival as using the log rank test (p< 0.02). TLR4 KO mice treated with APAP were protected from liver necrosis and had significantly better survival than wild type controls (p < 0.002). Conclusion: These data provides evidence for an important of TLR4 in APAP induced ALF and provide the rationale for a clinical trial of this strategy in ALF.

Thirty children received 35 liver transplants for fulminant or late-onset liver failure between March 1988 and May 1993. Aetiology included non-A non-B hepatitis in 12, Wilson's disease in 8, drug-induced hepatic failure in 6, hepatitis B in 1, hepatitis A in 1, tyrosinaemia in 1 and congenital haemochromatosis in 1. Three patients were retransplanted, one each for hepatic artery thrombosis, non-A non-B graft reinfection, and chronic rejection. Two of these three patients received a third transplant for chronic rejection and hepatic artery thrombosis. One patient in the retransplant group survived. Overall, graft and patient survival at a mean follow-up of 17 months were 49% and 57%, respectively. Mortality was related to vascular complications in three patients (hepatic venous obstruction, portal vein thrombosis and hepatic artery thrombosis). Two patients died of primary sepsis (cerebral aspergillosis and cytomegalovirus (CMV) pneumonitis in association with graft-versus-host disease). Systemic sepsis and multiorgan failure was documented as a cause of death in four children and sepsis in association with chronic rejection in a further three patients. One child died of respiratory failure 4 weeks after transplantation. Mortality in eight children less than 2 years was 75% and this was significantly greater than for older children (P < 0.003, Mantel Cox). Earlier referral, even in the absence of a definitive diagnosis and particularly in children under 2 years is advisable and may improve survival.

Introduction Severity of liver disease determines accurately the outcome of patients on liver transplant (LT) waiting list (WL). Comorbidities are known to affect post-LT outcomes but their effect on outcome of transplant assessment (TA) or WL mortality have not been fully explored in previous studies. Aim To study the impact of comorbidities on TA, WL mortality and post LT survival. Method Retrospective study of all patients assessed for LT at our centre between 1 January 2000 and 31 December 2007 (n=1484). Patients with acute liver failure (175), amyloid (43), those assessed for re-LT (149) and 24 with incomplete information were also excluded. Nine comorbidities (Charlson Comorbidity Index - CCI) were prospectively defined according to Volk et al ( Liver Transplant 2007; 13 :1515–20). Kaplan–Meier analysis was performed to determine impact of comorbidity on outcome. Cox regression hazard analysis was used to determine predictors of outcome and presented as (OR, 95% CI, p value). Results We analysed 1093 patients. Median age was 54 years (17–84), 67.5% were men (738). There were 192 (17.6%) patients with hepatocellular carcinoma (HCC). Patients with ≥1 comorbidity were 499 (46.6%) with most common comorbidities being diabetes (23.2%) and renal dysfunction (12.1%). Of 1093 assessed patients, 826 (75.6%) were listed. Patients with ≥1 comorbidity had significantly decreased LT free survival (log rank =33.586, p Conclusion We demonstrate that comorbidities significantly impact on the outcome of patients with chronic liver disease at TA, on wait-list and post LT survival. Adding CCI to known liver prognostic models may improve their prediction ability.

Introduction Current super urgent criteria for listing for early liver graft dysfunction (ELGD) in the UK (category 9, C9C) is defined as fulfilling 2 out of 4 of the following criteria within 7 days post liver transplant (LT): AST >10 000IU/l, INR >3, Lactate >3 mmol/l and absence of bile production. We demonstrated that these criteria have critically low sensitivity in predicting early post LT death or need for re-LT (Al-Freah, et al. Hepatology 2009; 50 Suppl 4:A148). Aim To develop an improved predictive model for early re-LT or death using early post-LT clinical parameters. Method Retrospective study of all patients transplanted at our centre 1 January 2000 to 31 December 2008. Daily clinical and laboratory parameters for the first 7 days post LT were reviewed. These included AST, bilirubin, INR, lactate, vasopressor requirement and/or haemofiltration. Results Over the study period, 1286 patients underwent first LT at our centre. Patients excluded (28) because of re-LT for hepatic artery thrombosis (22), died on table (5) and one re-LT because of donor cancer. We analysed data on 1258 patients (median age 51 (16–74) years (16–74), 60% male). The most common aetiology was viral hepatitis in 303 patients (24%) and alcohol related liver disease in 227 patients (18%); 181 patients (14.4%) with hepatocellular carcinoma. Median MELD score was 16 (6–40). Death or re-LT rate at 3 months was 9.9% (124). Only 27 (2.1%) fulfilled C9C at 3 months: 17 (63%) of those died or had re-LT within 3 months (p 3 mmol/l, D7 AST >500 IU/l and D7 bilirubin >100 μmol/l. Those scored 1, 2, 3, 4 or 5 points had OR of risk of death/re-LT within 3 months of 1.26 (0.897–1.766, p=0.184), 1.345 (0.8817–2.051, p=0.171), 2.811 (1.669–4.732, p=0.0001), 15.561 (7.425–32.611, p

Summary Fungal infections following liver transplantation are not uncommon and may be life-threatening. Superficial candidal infections of the bronchus, oesophagus and urinary tract are the most common mode of presentation. Invasive cutaneous and subcutaneous candidiasis is, however, very rare. We report two patients with invasive cutaneous and subcutaneous candidiasis after orthotopic liver transplantation.

Introduction The liver is frequently involved in systemic AL amyloidosis in association with B-cell dyscrasias, and some of the hereditary forms mainly apolipoprotein ApoAI amyloidosis. Extensive hepatic amyloid infiltrate can lead to liver failure. We report here the features, disease course, management and outcome of 28 patients with end-stage hepatic amyloidosis. Methods Twenty-eight patients with amyloid related liver failure, median age 53 (28–70) years. All patients had hepatomegaly, 14 (50%) had jaundice, ten had ascites, four patients had encephalopathy, and three were in renal failure. The amyloid type was determined by immunohistochemistry, serum/urine electrophoresis and DNA analysis. All patients had comprehensive systemic, cardiac and neurological evaluation. Results 22 patients had AL amyloidosis due to B-cell dyscrasias; none were eligible for chemotherapy. Six cases had hereditary amyloid due to variant fibrinogen A α chain, AFib (1) and apolipoprotein ApoAI (5). Extrahepatic amyloid deposits were present in all cases. 11/22 patients with AL liver failure were listed for liver transplantation (LT). All six patients with ApoAI or AFib amyloidosis who had liver and renal failure were considered for combined liver/kidney transplant (LKT). Nine AL patients received LT as a rescue procedure and two died with complications of hepatic rupture or multi-organ failure on the waiting list. The remaining 11 AL cases all died within 2–16 weeks with progressive cholestasis and subacute liver failure. Actuarial 1-year survival post LT in AL was 75%, 2-year 50%. Early mortality post LT was due to septic episodes, nephrotic syndrome and renal failure, and medium-term due to progressive amyloidosis and multiple organ falure. Only two AL patients exhibited over 5 year survival. Both had predominantly liver and splenic amyloid with no cardiac or renal involvement and were treated with stem cell transplant (SCT) after LT. Three ApoAI cases had successful LKT but two died with complications of liver failure on the wait list. The AFib patient has normal graft function at 13 years post LKT (cumulative LKT survival for ApoAI and AFib 100%). Conclusion LT is life saving for liver failure due to AL amyloidosis, but the outcome is ultimately determined by severity of systemic disease at the time of LT and eligibility for efficient treatment for AL after LT. Sequential SCT was associated with long-term remission in two LT recipients. The excellent outcome of LT in both ApoAI and AFib hereditary systemic amyloidosis strongly supports its use for these indications.

The mortality rate of fulminant hepatic failure (FHF) in childhood has remained between 70% and 95% despite recent improvements in medical therapy. Liver transplantation has become an important therapeutic option in adults with this entity, but has been infrequently performed in children. Many children do not receive transplants because of the rapid progression of the illness and the lack of suitable donor livers. We present our experience in liver transplantation in children with FHF. Between March 1988 and December 1989, seven children aged between 15 months and 12 years received eight liver transplants. The aetiology of FHF was viral hepatitis in five and drug hepatotoxicity (carbamazepine) in two. Five of our patients were in grade III-IV coma. Reduced-sized livers were used in six of the eight transplants. The post-operative morbidity included viral and fungal infections, and abdominal bleeding. Two patients died from graft-versus-host disease and one from brain aspergillosis. Four patients (57%) survived a median follow-up of 15 months. Liver transplantation should be the therapeutic option in children with FHF where the chances of medical recovery are poor.

Focal nodular hyperplasia is a benign liver tumour that is rare in children. We report the second case of a child with sickle cell disease presenting with symptomatic focal nodular hyperplasia. The possible pathogenesis of focal nodular hyperplasia and the association with sickle cell disease are discussed.

The technique of selective arterial embolisation for patients presenting with major hepatic trauma is described. We have used this technique successfully in four patients, three of whom had continued bleeding after emergency laparotomy. It can abolish localised intrahepatic arterial haemorrhage and arteriovenous shunting. Selective embolisation may prove to be a useful technique in reducing the mortality of major hepatic trauma.

Bilateral vasa aplasia is considered an invariable finding in cystic fibrosis, but such patients are rarely seen in male infertility clinics. The improved survival beyond 20 years of age is likely to change this. In a clinical study of a group of male cystics the vasa were absent in 8 of 11 boys and epididymal abnormalities were palpable in the majority. The main cause of infertility appears to be mechanical obstruction. Whether the absence is due to a primary failure of mesonephric duct development or secondary to luminal obstruction and subsequent atrophy is not known.

Summary Drug smuggling by internal bodily concealment is a growing international problem. The management of a patient who swallowed packages containing heroin is described. The medical management, indications for surgery and the ethical dilemmas of treating patients with drugs concealed within the gastrointestinal tract are discussed.