925 FACTORS ASSOCIATED WITH POOR OUTCOME IN PRIMARY BILIARY CIRRHOSIS M. Carbone, G. Mells, H.J. Cordell, M.A. Heneghan, J.M. Neuberger, P.T. Donaldson, A.J. Bathgate, A.K. Burroughs, M.H. Davies, D.B. Day, S. Rushton, M.F. Dawwas, S. Thomson, G.J. Alexander, D.E. Jones, R.N. Sandford, UK Primary Biliary Cirrhosis (PBC) Consortium. Academic Department of Medical Genetics, University of Cambridge, Department of Medicine, Division of Gastroenterology and Hepatology, Cambridge University Hospitals, Cambridge, Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, Institute of Liver Studies, King’s College Hospital, London, Liver Unit, Queen Elizabeth Hospital, Birmingham, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, Liver Transplantation and Hepato-Biliary Medicine Unit, Royal Free Hospital, London, Liver Unit, St James’s University Hospital, Leeds, Organ Donation and Transplantation, NHS Blood and Transplant, Bristol, UK E-mail: marco.carbone@uniroma2.it

PRESENTATIONSpatients who underwent LT for PSC in 10 German transplant centers between 01/1990 and 12/2006.Statistical analyses were performed using Mann-Whitney-and chi-square-test.Results: 335 patients (68.4% men, mean age 38.9 years, 73.5% with IBD) were transplanted 8.5 years (mean) after initial PSC diagnosis and followed for 98.6 months (mean, range 0-266).The one-year, five-year-and overall recipient and graft survival was 90.7%, 84.7%, 76.1% and 79.1%, 69.0%, 59.4% respectively.After exclusion of patients with a graft follow up < 6 months (n = 68), with missing clinical information (n = 22) and with recurrent cholangiocarcinoma (n = 6) we found that 44% of the remaining 239 patients developed biliary strictures.After further exclusion of 48 patients with arterial complications, chronic ductopenic rejection, pure anastomotic strictures or early (<90days) intrahepatic strictures we diagnosed recurrent PSC in 32% (18.5% of the overall study cohort).We identified the following significant (p < 0.05) risk factors of recurrent PSC: higher MELD-or Mayorisk-Score at LT, male sex, IBD, active colon-inflammation following LT, more than one episode of acute rejection.Furthermore arterial complications and a chronic ductopenic rejection were significantly associated with overall biliary strictures.Conclusions: This so far largest study on the long-term outcome of LT for PSC confirms some of the clinical risk factors of PSC recurrence like acute cellular rejections and colon inflammation and identifies additional new risk factors.These findings might help to optimize the pre-and post-LT-management of PSC.

Background: Although renal dysfunction is a common complication of acute liver failure (ALF) with significant prognostic implications, the pathophysiological mechanisms remain unclear. The current hypothesis suggests that the renal dysfunction may mirror the hepatorenal syndrome of cirrhosis. However, ALF has distinct clinical characteristics and the circulatory derangement may be more comparable with sepsis.Objectives: To examine the relationship between the systemic inflammatory response syndrome (SIRS) and renal dysfunction in ALF, and to identify additional risk factors for renal dysfunction.Methods: A single-centre retrospective study of 308 patients with ALF was carried out. Renal dysfunction was defined according to the RIFLE criteria for acute kidney injury.Results: 67% of patients developed renal dysfunction. On univariate analysis, renal dysfunction patients were more likely to be hypothermic (p = 0.010), had a faster heart rate (p < 0.001), a higher white cell count (p = 0.001) and a lower PaCO2 (p = 0.033). 78% of renal dysfunction patients and 53% of non-renal dysfunction patients had SIRS (p < 0.001). On multivariate analysis, the risk factors for renal dysfunction were age (p = 0.024), fulfilled Kings College Hospital prognostic criteria (p < 0.001), hypotension (p, 0.001), paracetamol-induced ALF (p < 0.001), infection (p = 0.077) and SIRS (p = 0.017). SIRS remained an independent predictor of renal dysfunction in the subgroup of patients with non-paracetamol-induced ALF (n = 91, p = 0.001). In contrast, in patients with paracetamol-induced ALF (n = 217), no relationship between SIRS and renal dysfunction was demonstrated (p = 0.373).Conclusion: SIRS is strongly associated with the development of renal dysfunction in patients with non-paracetamol-induced ALF. It is proposed that the systemic inflammatory cascade plays a key role in its pathogenesis.

We describe the case of a gentleman who initially presented with isolated cranial diabetes insipidus and has subsequently developed progressive anterior pituitary failure. In addition, he has been found to have evidence of mesenteric fibrosis and primary sclerosing cholangitis. We suggest that his pituitary disease may also be caused by progressive fibrosis and that these separate pathological entities may be linked by the unifying diagnosis of progressive multifocal fibrosclerosis, a rare fibro-inflammatory process involving multiple organ systems.

AIMS:To determine whether C4d immunopositivity helps recognition of humoral rejection in dysfunctional liver allografts. METHODS AND RESULTS:C4d immunopositivity was retrospectively evaluated in liver allografts. There were three staining patterns: portal venular plexus, sinusoidal and hepatocellular. The latter was related to ischaemic necrosis and not scored as positive. C4d immunopositivity was not encountered in 10 preperfusion or 15 consecutive early protocol biopsies. However, three of 12 early protocol biopsy specimens from crossmatch-positive patients were C4d+, two showing repeated positivity on at least one further biopsy specimen, while others remained negative. C4d was also positive in 2/16 early moderate acute cellular rejections, 3/14 cases of centrilobular necroinflammation, 3/11 biliary obstructions, 3/13 chronic rejections and 1/10 primary non-functional allografts. CONCLUSION:C4d immunopositivity is uncommon in liver allografts. There is a weak positive correlation with a positive lymphocytotoxic crossmatch and some patterns of allograft dysfunction. The morphological associations resemble those reported in lymphocytotoxic crossmatch-positive patients, plus occasional sinusoidal and hepatocellular injury. Although the practical utility of C4d immunohistochemistry seems limited, it may identify a small subgroup of individuals in whom chronic humoral microvascular injury contributes to allograft dysfunction.

Traumatic cholecystectomy is a rare condition that has always been described in the context of major trauma and associated liver or biliary injuries. We present a case of isolated traumatic cholecystectomy following a trivial injury which resulted in both a delayed presentation and a difficult diagnosis.

Current accepted treatment for chronic hepatitis B uses either the immunomodulator interferon alpha or nucleoside analogues lamivudine or adefovir. Interferon has side effects which mean it is often poorly tolerated. Long-term use of lamivudine is associated with increasing viral resistance for each year it is taken and the rebound viraemia that can occur when the drug is stopped is also of concern to many. Adefovir appears to have less of the resistance issues of lamivudine but is still a relatively new drug and at present its use is principally limited to patients with lamivudine-resistant disease. A number of other nucleoside analogues are currently being developed with some now at the stage of early clinical trials. A proportion share the significant resistance problems of lamivudine but many appear to have more potent anti-viral effect than the drugs currently available. If some of these newer anti-viral agents are approved for use in chronic hepatitis B, the potential for prolonged suppression of hepatitis B virus replication with resultant stabilization or improvement in liver disease may be achieved.

OBJECTIVE:To determine the spectrum and outcome of colorectal diseases occurring in adult liver allograft recipients. DESIGN:A retrospective cohort analysis of clinical, microbiological and histopathological data regarding colorectal disease. PATIENTS:Forty three out of 302 adult primary liver allograft recipients were transplanted and followed up (at median 42 months) at a tertiary referral centre/teaching hospital. RESULTS:Out of 302 patients, 43 (14%) were investigated (by endoscopy and/or laparotomy) for symptoms of colorectal disease after orthotopic liver transplantation. The symptoms were: diarrhoea (n = 31); per-rectal bleeding (n = 5); and symptoms relating to pre-transplant ulcerative colitis (n = 7). Among the patients without known ulcerative colitis, per-rectal bleeding occurring early after orthotopic liver transplantation was most commonly caused by cytomegalovirus colitis and carried a poor prognosis. Excluding ulcerative colitis, the commonest causes of diarrhoea were Clostridium difficile, cytomegalovirus infection and medications, particularly during the first 2 months after orthotopic liver transplantation. No cases of colorectal graft-versus-host disease, cryptosporidiosis, amoebiasis, atypical mycobacterial infection or post-transplant lymphoproliferative disease were demonstrated. The activity of pre-transplant ulcerative colitis was unchanged or increased after orthotopic liver transplantation. Two further patients developed new-onset ulcerative colitis after orthotopic liver transplantation. CONCLUSIONS:Ulcerative colitis, C. difficile, cytomegalovirus infection and medications are the commonest colorectal causes of morbidity after orthotopic liver transplantation. Adult liver allograft recipients are, however, unlikely to show certain large bowel diseases encountered in other immunosuppressed groups. Amongst non-ulcerative colitis patients, those presenting with diarrhoea show a good outcome with appropriate management, whereas those with per-rectal bleeding have a more guarded prognosis.

Paracetamol overdose Is the commonest cause of acute liver failure in the UK, which has led to measures to restrict Its sale. We aimed to establish whether changes In the referral of patients with paracetamol-induced acute liver failure have occurred since the Introduction of legislation. We compared data from patients admitted to the Scottish Liver Transplantation Unit in 1992-98 with those admitted in 1998-2001. The Incidence of paracetamol-induced liver failure, severity of patients' illness, and outcome did not differ between the groups. Patients with paracetamol-induced acute liver failure had higher Carstairs scores (1.99 [95% CI 1.33-2.65]; n = 190) than patients with non-paracetamol acute liver failure (0.02 [-0.79 to 0.84]; n = 68). We have shown an association between paracetamol-induced acute liver failure and social deprivation.

Immunosuppressive therapy has many adverse effects in both the short and longer term. Tailoring immunosuppression might be possible if pretransplantation parameters predicted rejection. We investigated production of the proinflammatory cytokine, tumor necrosis factor-α (TNF-α), and the anti-inflammatory cytokine, interleukin-10 (IL-10), pretransplantation to determine whether there is a relation with acute rejection. Peripheral-blood mononuclear cells were obtained from patients with chronic liver disease on the waiting list for orthotopic liver transplantation and healthy controls. Cells (0.5 × 106) were stimulated with 200 ng of lipopolysaccharide. Preincubation for 30 minutes with tacrolimus, cyclosporine, and dexamethasone at concentrations of 10 and 100 ng was also performed. TNF-α and IL-10 levels were measured by enzyme-linked immunosorbent assay. Acute rejection was defined on clinical and histological grounds. Pretransplantation in vitro production of TNF-α significantly (P < .05) increased in the group of patients with acute rejection (n = 9) compared with those who did not develop rejection (n = 12). Preincubation with dexamethasone significantly (P < .001) reduced TNF-α and IL-10 production in both patients and controls (n = 8). IL-10 production pretransplantation was not different in those who developed acute rejection (n = 9) compared with those who did not (n = 9). Preincubation with tacrolimus augmented (P < .05) the production of IL-10 in patients (n = 18), but not controls (n = 6). Pretransplantation TNF-α production is increased in patients who go on to develop acute rejection posttransplantion.

Objective To determine any relationship between polymorphisms in the genes encoding tumour necrosis factor alpha (TNF alpha), interleukin-10 (IL-10) and transforming growth factor beta1 (TGF beta1) and end-stage liver disease.Methods Whole-blood samples were taken from patients attending the Scottish Liver Transplant Unit with end-stage liver disease (primary biliary cirrhosis, n = 61; alcoholic liver disease, n = 25; primary sclerosing cholangitis, n = 17; viral disease, n = 8; type 1 auto-immune hepatitis, n = 8; acute liver failure, n = 20). DNA was extracted and the polymorphisms at positions TNF - 308, IL-10 - 1082 and TGF beta1 +869 and +915 were determined using sequence-specific oligonucleotide probes. Samples were also analysed from normal healthy controls.Results There was a significant difference between patients with primary sclerosing cholangitis and healthy controls, with 65% of patients (11/17) possessing at least one TNF2 allele (A at position -308) compared with 38% of controls (P = 0.02). Four of the eight patients with autoimmune hepatitis were homozygous for TNF2 while the other four were heterozygous (P = 0.001). No significant difference between controls and patients was seen in polymorphisms for IL-10 or TGF beta1. No association between genotype and Child's class was found in primary biliary cirrhosis.Conclusion Patients with primary sclerosing cholangitis and auto-immune hepatitis are more likely to possess TNF2 than normal controls. This allele has been associated with an increased production of TNF alpha in vitro and may indicate a predisposition to these inflammatory conditions. Eur J Gastroenterol Hepetol 12:1329-1333 (C) 2000 Lippincott Williams & Wilkins.

The occurrence of acute cellular rejection after orthotopic liver transplantation is common. At present, no allowance is made in immunosuppressive regimens for parameters other than weight. We investigated parameters in 121 consecutive patients receiving their primary allograft to determine if there are pretransplantation factors predicting the occurrence of acute cellular rejection after transplantation. The case notes and dietetic notes of these patients were reviewed for age at transplantation, cause of liver disease, preoperative albumin and creatinine levels, lymphocyte count, anthropometric measurements, donor age, HLA DR mismatch, and cold ischemia time. Acute cellular rejection was more likely to occur in younger patients, patients with Child's class A disease, and those with normal midarm muscle circumference. Acute rejection was increased in transplant recipients from donors aged younger than 30 and older than 50 years. Acute cellular rejection was less likely to occur in patients who underwent transplantation for alcoholic liver disease. Chronic rejection was significantly increased in women and those patients who experienced recurrent acute rejection. On multivariate analysis, the only significant predictor was the decreased likelihood of acute rejection in patients with depleted midarm muscle circumference. In conclusion, it may be possible to individualize immunosuppressive regimens on the basis of pretransplantation characteristics.

776 Orthotopic hepatic allograft failure can occur due to chronic rejection and occasionally due to acute rejection. The role of cytokines in both processes is not entirely clear. The aim of this study was to investigate the association between polymorphisms known to affect in-vitro production of certain cytokines and rejection. Method: Whole blood samples from 138 liver transplant patients (57 PBC,27 ALD, 17 PSC, 7 viral, 8 autoimmune, 13 acute liver failure, 5 cryptogenic and 4 others) were analysed along with 180 controls. DNA was extracted and the presence of polymorphisms in alleles coding for tumour necrosis factor alpha (position −308), transforming growth factor beta (codons 10 and 25) and interleukin 10 (positions −1082,−819 and −592) identified using sequence specific oligonucleotide probes. The diagnosis of acute cellular rejection was made on clinical, biochemical and histological grounds and was said to have occurred if high dose steroid was given. Chronic rejection was a histological diagnosis. Results: The table shows the occurrence of acute rejection with respect to TNFα genotype.TableThere was no significant differences between the rejection and non-rejection group with respect to Il-10 or TGFβ genotype polymorphisms. Chronic rejection was infrequent in the group as a whole (8/138). None of these patients had a genotype associated with low production of TGFβ. Conclusion: Acute cellular rejection is more common in patients with a polymorphism associated with high TNFα production.

The Scottish Liver Transplant Unit is now in its sixth year of existence. We present the outcome of the first 165 transplants which have at least 12 months follow up. The overall patient (n=143) survival rates at 1, 3 and 5 years were 86.6%, 79.3% and 74.7% and the graft survival rates were 76.9%, 69.1 % and 64.8%. The one year survival rate for patients with chronic liver disease (n=113) was 89.2% compared with 76.6% for acute liver failure (Breslow= 0.05). The one year survival rate for the first 71 patients receiving their primary graft was 81.7% compared with 91.5% for the subsequent 71 patients (Breslow = 0.09). The majority of deaths (n=29) were due to sepsis (n=7), at operation (n=6) or due to graft vascular insufficiency (n=4). There were two cases ofde novo haematological malignancy. The outcome of the first 165 transplants in Scotland compares very well with other countries throughout the world.