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We report the first successful use of hepatocyte transplantation as a bridge to subsequent auxiliary partial orthotopic liver transplantation (APOLT) in a child antenatally diagnosed with severe ornithine transcarbamylase (OTC) deficiency. A total of 1.74 x 10(9) fresh and cryopreserved hepatocytes were administered intraportally into the liver over a period of 6 months. Immunosuppression was with tacrolimus and prednisolone. A sustained decrease in ammonia levels and a gradual increase in serum urea were observed except during episodes of sepsis in the first 6 months of life. The patient was able to tolerate a normal protein intake and presented a normal growth and neurological development. APOLT was successfully performed at 7 months of age. We conclude that hepatocyte transplantation can be used in conjunction with APOLT as an effective treatment for severe OTC-deficient patients, improving neurodevelopmental outcomes.

Liver transplantation is the accepted treatment for a wide variety of liver diseases in children. Over the past 10 years a number of innovative surgical techniques have been developed to overcome the shortage of size matched donors particularly in children less than 5 years of age. Graft and patient survival at one year after liver transplantation has continued to improve, and is now over 85% and higher for good risk cases. Complications are relatively common, but provided graft function is satisfactory, long term survival for these children is to be expected. The need for retransplantation has fallen significantly. Causes of early mortality include graft dysfunction and sepsis. Late mortality is due to sepsis, post-transplant lymphoproliferative disease, and non-compliance. Long term survival with good graft function and excellent quality of life is possible for the majority of children undergoing liver transplantation.

Background. The role of interleukin-2 receptor antibodies as rescue therapy in steroid-resistant rejection (SRR) has not been studied. We evaluated the safety and efficacy of an interleukin-2 receptor antibody, basiliximab (Simulect, Novartis, East Hanover, NJ), in treating SRR in pediatric liver transplant recipients. Methods. This was a prospective study of seven pediatric liver transplant recipients with biopsy-proven SRR who would have otherwise received OKT3 or antithymocyte globulin. The primary immunosuppression consisted of cyclosporine (Neoral, Novartis), azathioprine, and prednisolone in four patients and tacrolimus and prednisolone in three patients who had undergone retransplantation for chronic rejection (n=2) and hyperacute rejection (n=1). Four patients had received two cycles of high-dose steroids, and three patients had received a single cycle; all had been converted to tacrolimus, followed by the addition of mycophenolate mofetil. Results. The median time from transplant to SRR was 30 days (range, 8 days–23 months). Five children received two doses of basiliximab (10 mg, 3–7 days apart), and two children received a single dose. Aspartate aminotransferase levels normalized in three children 12, 21, and 30 days after basiliximab treatment. Aspartate aminotransferase levels decreased without normalizing in two children, but there was no further evidence of cellular rejection on repeat biopsies. All five children are rejection-free with a median follow-up of 22 months (range, 5–32 months). Biochemical abnormalities persisted in the remaining two children, and both developed chronic rejection. There were no immediate side effects associated with basiliximab. Two patients were treated empirically for possible cytomegalovirus infection 21 and 57 days after basiliximab treatment, with no evidence of cytomegalovirus disease. Conclusion. Five of seven pediatric liver transplant recipients with SRR experienced successful outcomes with basiliximab treatment without major side effects, indicating that it is a safe alternative to OKT3 and other antilymphocyte antibodies.

Objective. To report our experience of prospectively identifying and transplanting livers into HIV-positive patients. Design. Liver transplantation in HIV-positive patients remains controversial. The finding of HIV is usually considered a contraindication to any form of transplantation. Previously reported cases are few and refer to patients who tested HIV positive after they had their liver transplantations or who seroconverted in the posttransplantation period. This is, to our knowledge, the only report of patients who were known to be HIV positive at the time of decision for listing for transplantation. Methods. The medical records of five HIV-positive patients who received liver transplants in King's College Hospital, London, during a 5-year period (January 1995-December 1999) were reviewed. All five were known to be HIV positive at the time of listing for liver replacement. Three of them had end-stage liver disease due to hepatitis C (two of them had underlying Hemophilia A) while the other two had acute liver failure, one due to hepatitis B infection and one due to nonA-nonB-nonC hepatitis. In all but one patient the HIV infection had been asymptomatic. Results. All patients survived the immediate posttransplantation period, but the three patients with hepatitis C died of complications of recurrent hepatitis C between 6 and 25 months posttransplantation. The other two patients are currently alive 4 and 34 months posttransplantation with good graft function and without complications from their HIV infection. Conclusion. The early outcome of liver transplantation in HIV seropositive patients can be good, and patients should not be excluded from transplantation if their liver disease determines their prognosis. More effective antiviral therapy for hepatitis C given posttransplantation, and for hepatitis B reinfection, should improve the longer-term outcome of HIV patients with end-stage liver disease due to hepatitis.

Background Circulating transthyretin (TTR) is derived from the liver, and orthotopic liver transplantation (OLT) is widely performed for variant TTR-associated familial amyloid polyneuropathy (FAP). The effect of OLT on FAP-related cardiac amyloid is of particular interest because wild-type TTR can itself be deposited as senile cardiac amyloid. Methods Serial echocardiography was performed in 20 FAP patients, 14 of whom underwent OLT, and 10 other liver transplant patients. Follow-up included serum amyloid P component scintigraphy and measurement of plasma TTR before and after OLT. Results Cardiac amyloidosis progressed rapidly in three FAP patients (TTR Pro52 and Thr84 mutations) after OLT, even though the deposits elsewhere had stabilized or regressed. Results of echocardiography improved in three transplant patients with TTR Met30 and remained normal in seven other patients. Plasma TTR levels were altered substantially after OLT, but they did not reflect the cardiac findings. Conclusions Although amyloid deposition in FAP is generally inhibited after OLT, cardiac amyloidosis can be exacerbated, probably due to enhanced deposition of wild-type TTR on a template of amyloid derived from variant TTR. The phenomenon may be mutation-dependent. These findings suggest that amyloid formation de novo and its subsequent accumulation can be promoted by different factors, which may be organ-specific.

Introduction Portal vein thrombosis (PVT) has multiple aetiologies which can lead to the development of portal hypertension and variceal bleeding. Data on the long term sequelae of PVT in paediatric and adolescent patients is limited. Methods Patients included had a diagnosis of PVT from Jan 2000- Dec 2014. Data collection included patient demographics, aetiologies, presentation and initial treatment of PVT. Data was also collected on further variceal bleeds, shunt surgery, liver transplantation and long term mortality. Results 123 patients (63 male) were identified. Median age at first presentation was 5years 9 months (range 2 days to 25 years). Overall survival was 95.9, 94.3 and 93.5% at 1, 10 and >20 years from PVT diagnosis, respectively. Median age at follow up was 13years 3 months (range 6 months to 33 years 2 months). In the majority of cases (52%) no cause for PVT was identified. 78% of patients had extrahepatic PVT (EHPVT), with no extension in to the superior mesenteric vein. 19 patients (15.4%) were anticoagulated or had received a course of anticoagulation therapy. Initial presentation was usually due to oesophageal variceal bleeding (52.8%) of which 24 patients had further variceal bleeds (18.7%, oesophageal/duodenal/rectal). At follow up, 26% of patients (N = 32) were on a beta blocker. Of these, 10 patients (31.3%) had further variceal bleeds versus 14/77 patients, not on a beta blocker (18.2%, p = 0.07). Portal biliopathy was also present in 17.9% (N = 22) as was splenomegaly (82.9%). Ascites and hepatic encephalopathy were uncommon ( Conclusion Oesophageal variceal bleeding is a common index presentation of PVT in paediatric and adolescent patients. Approximately 20% of patients will go on to have further variceal bleeds despite medical intervention. Beta blocker use is associated with recurrent variceal bleeding which may suggest that it is ineffective in preventing further variceal bleeding in patients with established portal cavernomas. Overall, long term survival is good. Disclosure of Interest None Declared

Occult myeloproliferative disorders (MPD) are present in 25% of patients with chronic portal, splenic and mesenteric venous thrombosis (PSMVT). A somatic mutation of JAK2 (JAK2V617F) can be used to identify patients with latent MPD.We evaluated the prevalence and clinical significance of JAK2V617F in patients with chronic PSMVT.Allele-specific polymerase chain reaction was performed to screen for JAK2V617F.Thirty-five patients were tested for JAK2V617F. The underlying pro-coagulant condition was MPD in seven of 35 (20.0%) patients; other aetiologies included hereditary thrombophilia (n = 5), chronic pancreatitis (n = 2), liver abscess (n = 1) and umbilical vein sepsis (n = 3). The remainder were labelled idiopathic, i.e. 17/35 (48.6%) patients. JAK2V617F was detected in 16/35 (45.7%) patients: seven of seven (100%) with MPD, two of 11 (18.1%) with non-MPD acquired conditions and seven of 17 (41.2%) with 'idiopathic' chronic PSMVT. Mean haemoglobin concentration (P = 0.04), haematocrit (P = 0.04), white cell count (P = 0.002) and platelet count (P = 0.05) were significantly higher in patients with JAK2V617F. None of the seven patients with latent MPD have progressed to overt MPD over median follow-up of 85 months.JAK2V617F occurs in 41% of patients with idiopathic chronic portal, splenic and mesenteric venous thrombosis, confirming the presence of latent myeloproliferative disorders, and should form part of the routine pro-coagulant screen.

Background: Despite its accuracy, the model for end-stage liver disease (MELD), currently adopted to determine the prognosis of patients with liver cirrhosis, guide referral to transplant programmes and prioritise the allocation of donor organs, fails to predict mortality in a considerable proportion of patients. Aims: To evaluate the possibility to better predict 3-month liver disease-related mortality of patients awaiting liver transplantation using an artificial neural network (ANN). Patients and methods: The ANN was constructed using data from 251 consecutive people with cirrhosis listed for liver transplantation at the Liver Transplant Unit, Bologna, Italy. The ANN was trained to predict 3-month survival on 188 patients, tested on the remaining 63 (internal validation group) unknown by the system and finally on 137 patients listed for liver transplantation at the King’s College Hospital, London, UK (external cohort). Predictions of survival obtained with ANN and MELD on the same datasets were compared using areas under receiver-operating characteristic (ROC) curves (AUC). Results: The ANN performed significantly better than MELD both in the internal validation group (AUC = 0.95 v 0.85; p = 0.032) and in the external cohort (AUC = 0.96 v 0.86; p = 0.044). Conclusions: The ANN measured the mortality risk of patients with cirrhosis more accurately than MELD and could better prioritise liver transplant candidates, thus reducing mortality in the waiting list.

Introduction Hepatocellular carcinoma (HCC) rates are higher in patients with hereditary haemochromatosis (HH) compared to other aetiologies. Survival with or without liver transplantation (LT) is often deemed less favourable. Modern mortality rates post LT or following loco-regional therapy (LRT) are not well reported therefore prognostic pessimism may be misplaced. Method Consecutive patients with HH and HCC diagnosed between 2000 and 2013 at our institution were studied. Patients were offered curative liver transplantation (LT), radiofrequency ablation (RFA) or surgical resection; or, non-curative treatment with trans-arterial chemo-embolization (TACE), sorafenib or symptom control according to performance status and Barcelona Clinic Liver Cancer (BCLC) stage. Patient characteristics recorded at time of first HCC diagnosis included demographics, tumour size and multiplicity, severity of liver disease, serum ferritin (SF, as a proxy for HH treatment) and alphafetoprotein (AFP). The primary end-point was all-cause mortality. Results Forty-one patients (median (range) age 67(44–78) years, 97% male, MELD 8(5–31)) made up the study cohort with a median follow up of 22(3–126) months. Thirty-six patients had cirrhosis and median SF was 256(27–5718) mg/L and median AFP 29(2–197926) kIU/L. Twenty-seven (66%) patients had solitary tumours, 44% were BCLC stage A, 27% BCLC-B, 10% BCLC-C and 5% BCLC-D. TACE was the commonest LRT choice in 21 (49%) patients. Four patients (9%) underwent surgical resection and RFA was performed in 5 (12%) patients. Fourteen patients (32%) underwent LT. Median survival was 27 (95% CI 17–41) months. Patients with >1 HCC did not have decreased survival compared to those with a single tumour (p = 0.386). Five-year survival for patients receiving curative therapy was 77% (80% for LT, 67% for surgery/RFA), and for those undergoing non-curative therapy 5-year survival was 15% (23% for patients receiving TACE). For BCLC-A patients 5-year survival was 64%, 50% for BCLC-B patients and 9% for BCLC-C/D patients (p = 0.002). On age-adjusted Cox regression survival analysis BCLC-C/D stage was independently associated with poor survival (Hazard Ratio 4.05 (1.29–12.63), p = 0.016) but not serum AFP, SF or the presence of cirrhosis. Conclusion Patients with HCC in the context of HH can achieve comparable survival rates following curative modalities to those with other aetiologies. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients. Disclosure of interest None Declared.

Background The potential for immunosuppression withdrawal is the rationale for auxiliary liver transplantation (AUX) in patients with acute liver failure (ALF). Patients and methods Forty-four AUX were performed in 28 adults and 16 children with ALF secondary to seronegative hepatitis (n = 20; 45%), paracetamol hepatotoxicity (n = 14; 32%), acute viral hepatitis (hepatitis B virus [HBV] n = 3, Epstein-Barr virus n = 1; 9%), drug-induced hepatitis (n = 3; 7%), autoimmune hepatitis (n = 2; 5%), and mushroom poisoning (n = 1; 2%). All patients fulfilled the King’s College Hospital transplant criteria for ALF. After partial hepatectomy, 38 patients received a segmental auxiliary graft and six, a whole auxiliary graft. Immunosuppression was based on calcineurin inhibitors and steroids. Results Thirty-four patients (77%) are alive after a median follow-up of 30 months (range 4 to 124). Eight adults and two children died of sepsis (n = 6; 14%) at a median interval of 30 days (range 2 to 66), intraoperative cardiac failure (n = 1), brain edema on postoperative day 8 (n = 1), sudden death on day 35 (n = 1), and multiple organ failure associated with HBV recurrence 4 years after transplantation (n = 1). Three patients underwent retransplantation for small-for-size graft syndrome with sepsis on postoperative day 15 (n = 1) and for ductopenic rejection 4 and 15 months after AUX (n = 2). In 10/31 (32%) survivors (6/18 adults and 4/13 children) immunosuppression was completely withdrawn after a median of 19 months. Conclusion Complete immunosuppression withdrawal can be achieved in a significant proportion of patients after AUX for ALF.

Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e31829791a2 1Department of Hepatology, Imperial College London, London, UK. 2Institute of Liver Studies at King’s College School of Medicine at King’s College Hospital, London, UK. 3Institute of Human Health and Performance, University College London, London, UK. 4Department of Asthma Allergy and Lung Biology, King’s College London, London, UK. 5Division of Critical Care Medicine, University of Alberta, Edmonton, Canada. Drs. Possamai and McPhail are joint first authors and Drs. Wendon, Mitry, and Antoniades are joint senior authors. Supported, in part, by the Imperial National Institute of Health Research Biomedical Research Centre for infrastructure and the King’s College Hospital Research & Development Department and Institute of Liver Studies Histopathology Department for ongoing support and the Medical Research Council UK. Dr. Possamai has received grant funding from the UK MRC. Dr. McPhail received funding from the Wellcome Trust UK as part of a Postdoctoral Training Fellowship [090542] during the production of this article. Dr. Abeles received NIHR-Doctoral Research fellowship from October 2009 to October 2010 and the fellowship had a travel allowance; he also received an EASL young investigator travel grant 2011 and 2012. Dr. Leslie holds multiple operating grants. Dr. Ma has received funding from the National Institutes of Health, Wellcome Trust, and the Howard Hughes Medical Institute. Dr. Shawcross is an advisory board member at Norgine, has given expert testimony for Talbot Walker LLP and Cooperative Legal Services, and has received grant support from HEFCE Clinical Senior Lectureship and Royal Society Grant. She has received payment for lectures from Frontiers in Hepatology and was sponsored to attend the European Association for the Study of the Liver 2011 by Bristol Myers Squibb. Dr. Bernal was a case review consultant for the University of Bordeaux in 2011 and received a speaking fee from the Cardiovascular Society of India in 2011. Dr. Dharwan has consulted for Boherenger Ingelham Cytonet, has received grant support from Astellas, has received payment for lectures from AASLD and EASL, and receives royalties from Oxford University Press. Dr. Heaton is a consultant for Astellas/Novartis and has received payment for lectures and payment for the development of educational presentations from Astellas. Dr. Thursz is a board member for the European Association for Study of the Liver, is a consultant for Abbott Pharmaceuticals, and has received payment for lectures from Gilead, BMS, and Janssen; he has also received travel reimbursements from Merck. Dr. Wendon has consulted for KASE A Kasai-Asai and is on the medical advisory board for Pulsion and Excalenz. Dr. Antoniades has received grant support from EASL Physician Scientist Fellowship Character and Temporal Evolution of Apoptosis in Acetaminophen-Induced Acute Liver Failure

The incidence of hepatic artery thrombosis (HAT) following orthotopic liver transplantation in children varies from 4% to 26% and represents a significant cause of graft loss. The purpose of this study was to analyze the risk factors for HAT following liver transplantation in children less than 5 years old. Seventy-three transplants were performed in 62 children under 5 years of age, including 16 for acute hepatic failure, 46 for chronic liver disease, and 11 retransplants. Twenty-four whole liver grafts (WLG) and 49 reduced size grafts (3 right lobes, 16 left lobes, and 30 left lateral segments) were transplanted. The recipient common hepatic artery was used to provide arterial inflow in 22 transplants and an infrarenal iliac conduit in 51 transplants. The overall incidence of HAT was 8 out of 73 transplants (11%). The cold ischemia time (14.3 +/- 3.03 hr) in this group was significantly longer than the cold ischemia time for those without HAT (11.7 +/- 3.94 hr) (P = 0.049). The incidence of HAT for whole and reduced grafts was 25% (6/24) and 4% (2/49), respectively (P = 0.01). HAT occurred in 6 of 22 grafts (27.3%) revascularized from the recipient common hepatic artery, compared with 2 of 51 grafts (3.9%) using an infrarenal arterial conduit (P = 0.008). The combination of recipient hepatic arterial inflow to a WLG resulted in HAT in 50% (6/12), whereas there were no cases of HAT with an iliac conduit to a WLG (P = 0.01). Of the eight patients with HAT, five are alive (median follow-up, 20 months; range, 7-27 months). Five patients were retransplanted, three within the first 2 weeks and two at 4 and 5 months for abnormal liver function in association with clinical and histological features of chronic rejection. Prolonged cold ischemia time and use of a whole graft with recipient hepatic arterial inflow are risk factors for developing HAT. The use of reduced size grafts and infrarenal iliac arterial conduits are associated with a low incidence of HAT.

Extrahepatic biliary atresia is the most common indication for liver transplantation in children. Coexistent congenital anomalies are common (25%), but the combination of polysplenia syndrome (10%) and absence of portal vein is rare.We report a case of successful reduced size liver transplantation on a 13-month-old girl with extrahepatic biliary atresia, polysplenia syndrome and congenital absence of the portal vein.Technical and post-operative problems related to absence of the portal vein and polysplenia are described and the literature reviewed.The donor portal vein was successfully anastomosed to the confluence of the superior mesenteric vein and splenic vein. The child is well with good graft function at a follow-up of 20 months.Absence of the portal vein and polysplenia syndrome is not a contraindication for liver transplantation although an increased post-operative morbidity may be expected.

The role of interleukin-2 receptor antibodies as rescue therapy in steroid-resistant rejection (SRR) has not been studied. We evaluated the safety and efficacy of an interleukin-2 receptor antibody, basiliximab (Simulect, Novartis, East Hanover, NJ), in treating SRR in pediatric liver transplant recipients.This was a prospective study of seven pediatric liver transplant recipients with biopsy-proven SRR who would have otherwise received OKT3 or antithymocyte globulin. The primary immunosuppression consisted of cyclosporine (Neoral, Novartis), azathioprine, and prednisolone in four patients and tacrolimus and prednisolone in three patients who had undergone retransplantation for chronic rejection (n=2) and hyperacute rejection (n=1). Four patients had received two cycles of high-dose steroids, and three patients had received a single cycle; all had been converted to tacrolimus, followed by the addition of mycophenolate mofetil.The median time from transplant to SRR was 30 days (range, 8 days-23 months). Five children received two doses of basiliximab (10 mg, 3-7 days apart), and two children received a single dose. Aspartate aminotransferase levels normalized in three children 12, 21, and 30 days after basiliximab treatment. Aspartate aminotransferase levels decreased without normalizing in two children, but there was no further evidence of cellular rejection on repeat biopsies. All five children are rejection-free with a median follow-up of 22 months (range, 5-32 months). Biochemical abnormalities persisted in the remaining two children, and both developed chronic rejection. There were no immediate side effects associated with basiliximab. Two patients were treated empirically for possible cytomegalovirus infection 21 and 57 days after basiliximab treatment, with no evidence of cytomegalovirus disease.Five of seven pediatric liver transplant recipients with SRR experienced successful outcomes with basiliximab treatment without major side effects, indicating that it is a safe alternative to OKT3 and other antilymphocyte antibodies.

Introduction The use of HBIG based prophylactic regimensto prevent recurrence of HBV in patients who have undergone LT is highly efficacious and well documented. However the long-term administration of HBIG can be time consuming, costly and inconvenient for the patient. With the advent of more potent oral anti-HBV agents the optimal long-term prophylactic strategy remains debatable. Aim A prospective single centre experience of switching from an intra-muscular (IM) HBIG based regimen to monotherapy tenofovir (TDF) or entecavir (ETV) to prevent HBV recurrence post LT. Method Patients receiving HBIG based prophylactic regimens were referred to a Pharmacist led clinic. Those with no serological evidence of HBV recurrence were considered for switch to monotherapy TDF or ETV. Decisions were based on clinical assessment and renal function, following an agreed stratified protocol. Data reported is an interim analysis 6 months post-switch. All results are presented as median. Results Patients: To date 29 patients have been switched. The median time since switch is 9 months. 25 patients are >6 months post switch and included in the analysis. The median age was 61 (range: 28–81) years, 84% male, 60% Caucasian, 28% Black African and 12% Asian. At LT 6 were acute HBV with Liver failure, 7 had HCC and 4 had delta co-infection. At LT 22 had detectable HBV DNA, 11 were on lamivudine (LAM) and 1 was on LAM and adefovir (ADV). 52% patients had archived samples suitable for drug resistance testing. None had evidence of any drug resistant mutations. Results: Since LT all had received HBIG IM with HBsAb levels of 170 (range 101–454) mIU/ml. 80% were receiving concurrent LAM, 4% LAM and ADV and 16% no oral anti-HBV agent. The median time from LT to switch was 10 (range 2.6–20.3) years. At switch HBsAg and HBV DNA was undetectable in all subjects. 92% were on calcineurin inhibitor based immunosuppressive regimens. Serum creatinine was 104 (range 62–170) μmol/l, estimated glomerular filtration rate (eGFR) was 65 ml/min, 24 h urine creatinine clearance was 76 (range 41–150) ml/min and total protein excretion was 81 (range 31–441) mg/day. Serum ALT was 26 IU/l, phosphate was 0.98 mmol/l and vitamin D was 14 μg/l. 12 had hypertension and/or diabetes. 16 patients were switched to TDF, 9 patients with eGFR Conclusion A stratified conversion protocol, based on the assessment of virological parameters and renal co-morbidities, ensures patients can safely and effectively be switched from HBIG to TDF or ETV to prevent HBV recurrence post LT. HBsAg and HBV DNA remains undetectable and no deterioration in renal function has been observed to date. Significant drug cost savings can be achieved utilising this protocol.

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 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.

Introduction Monocytes from patients with acetaminophen-induced acute liver failure (AALF) bear striking phenotypic and functional similarities with endotoxin tolerant (ET) monocytes and may account for the marked predisposition to sepsis and increased mortality in AALF. ET reprograms monocyte responses in response to lipolysaccharide (LPS) stimulation by reducing expression of pro-inflammatory (eg, TNF-α, IL-6) and augmenting the production of anti-inflammatory cytokines (eg, IL-10). At a molecular level, reductions in positive regulators (eg, NF-kBp65) of toll-like receptor (TLR)-4 dependent signalling pathway typify ET. Soluble anti-inflammatory mediators, such as IL-10 and SLPI, exert negative regulation of TLR responses via STAT3 and NF-kBp65 dependent signalling pathways respectively. Aim To delineate the molecular mechanisms and functional consequences of ET in AALF. Method Following TLR-4 (LPS; 100 ng/ml), IFN-γ (10 ng/ml) and IL-10 (50 ng/ml) stimulation, phosphoflow technique was used to identify changes in regulators of TLR (NF-kBp65, MAPK p38), STAT-1 and STAT-3 signalling pathways in ex-vivo CD14+/CD33+ monocytes in eight AALF patients and 10 healthy volunteers (HC). Results expressed as MFI and ratio of activation (MFI following LPS/IFN-γ/IL-10 stimulation divided by baseline MFI [RPMI]). Serum TNF-α, IL-10 and SLPI were measured by ELISA (pg/ml) in 34 AALF patients and 15 healthy volunteers (HC). Regional levels of TNF-α, IL-10 and SLPI (portal vein [PV]), hepatic vein [HV]) were determined using in a further five AALF patients at time of liver transplantation (LT). Hepatic expression of TNF-α, IL-10 and SLPI (all pg/ml below) was determined using whole liver tissue homogenates from seven AALF explants and eight controls. Ex-vivo monocyte phagocytosis of FITC-labelled Escherichia coli was determined in five AALF and 10 healthy volunteers (HC) using FACS analysis. Results In contrast to HC, TLR-4 stimulation markedly reduced NF-kBp65 expression, while MAPKp38 signal transduction responses remained similar to that of HC (Abstract P95 figures 1–2). Baseline STAT-3 expression was significantly elevated in AALF patients compared to HC whereas no differences in STAT-1 expression was detected (Abstract P95 figure 2). Increase in STAT-3 expression following IL-10 stimulation was similar between AALF patients and HC. AALF patients had significantly higher serum concentrations of TNF-α (21 vs 1.5; p PV) gradient was seen for IL-10 and SLPI but not for TNF-α in 4 out 5 AALF patients sampled (Abstract P95 figure 3). Intra-hepatic levels of IL-10 (2 vs 0.6; p=0.03) and SLPI (442 vs 116; p=0.004) were higher in patients with AALF compared to controls, whereas no difference in TNF-α (24 vs 19; p=0.3) concentration was detected. The percentage of monocytes phagocytosing E coli was significantly reduced in ALF compared to HC (69 vs 92%; p=0.008). Conclusion In AALF, circulating monocytes show modulations in intracellular signalling pathways compatible with ET and display reduced phagocytic capabilities. Our data also indicate that hepatic production of anti-inflammatory mediators, IL-10 and SLPI, may play a pivotal role in induction of ET monocytes and thus increase the risk of infection in AALF.

Treatment of systemic amyloidosis comprises measures to support failing organ function coupled with attempts to reduce the supply of the respective amyloid fibril precursor protein. Orthotopic hepatic transplantation is effective in familial amyloid polyneuropathy associated with variant transthyretin, because this protein is produced almost exclusively in the liver. Hepatic transplantation has not been performed in hereditary apolipoprotein AI (apoAI) amyloidosis, and the liver's contribution to plasma apoAI levels has not been determined in vivo.A 57-year-old Irish man with hereditary systemic amyloidosis associated with apoAI Gly26Arg, which had led to end-stage renal failure and progressive liver dysfunction, underwent hepatorenal transplantation. His outcome was followed clinically and his amyloid deposits were monitored with serum amyloid P component scintigraphy. The proportion of variant apoAI in the plasma was estimated by quantitative isoelectric focusing before and after liver transplantation.Plasma levels of variant apoAI decreased by 50% after liver transplantation, and the patient was asymptomatic 2 years after surgery. Subclinical amyloid deposits that were present in his spleen and heart preoperatively have regressed and stabilized respectively.Orthotopic liver transplantation substantially reduces the supply of the amyloid fibril precursor protein in hereditary apoAI amyloidosis, and the excellent outcome in this patient probably reflects the balance between deposition and turnover of amyloid having been altered in favor of the latter. These findings support the use of liver transplantation in patients with hereditary apoAI amyloidosis who develop hepatic dysfunction.

The hyper-IgM syndrome, a rare form of combined primary immunodeficiency, is characterized by neutropenia and defective B-cell isotype switching, which results in elevated or normal levels of serum IgM and low levels of serum IgG, IgA, and IgE.1 Clinically, patients with the syndrome have serious pyogenic infections caused by encapsulated bacteria, suggestive of the presence of humoral immunodeficiency. They are also susceptible to infections with intracellular pathogens such as Pneumocystis carinii, Cryptosporidium parvum, and leishmania, because of a possible defect in cellular immunity.2,3 The inheritance is usually X-linked, but autosomal recessive and autosomal dominant forms have also been documented. . . .

After observing micro-bubble activity in the venovenous bypass system during liver transplantation, an experiment was designed to investigate the origin of these bubbles and to define the conditions under which they occurred. Using a Biomedicus constrained vortex pump and a customized circuit design, microbubble activity was measured in saline and blood media during varying pre- and post-head pressures. The data show that air emboli can be generated from this pump and the rate at which they develop is directly related to the pre- and post-head pressure and hematocrit.

Diaphragmatic paralysis was identified in four children after liver transplantation. All presented with persistent right upper lobe atelectasis, pleural effusion and recurrent respiratory infections and could not be weaned from mechanical ventilatory support. Fluoroscopy and real-time ultrasound confirmed paradoxical right diaphragmatic movements. Diaphragmatic plication was undertaken and enabled rapid and sustained weaning from respiratory support in all four cases. Vascular clamping of the suprahepatic vena cava seems to be the cause. Diaphragmatic plication allows optimal recruitment of the respiratory muscles with a favourable impact on lung mechanics and gas exchange.