The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure.

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 PaCO(2) (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.

Multifocal fibrosclerosis: a new case report.

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.

C4d immunopositivity is uncommon in ABO-compatible liver allografts, but correlates partially with lymphocytotoxic antibody status.

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.

Review article: Nucleoside analogues for the treatment of chronic hepatitis B.

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.

Avulsion of the gallbladder following trivial injury.

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.

Referral patterns and social deprivation in paracetamol-induced liver injury in Scotland.

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.

Pretransplantation tumor necrosis factor-alpha production predicts acute rejection after liver transplantation.

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-alpha (TNF-alpha), 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 x 10(6)) 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-alpha 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-alpha 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-alpha 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-alpha production is increased in patients who go on to develop acute rejection posttransplantion.

The effect of polymorphisms in tumor necrosis factor-alpha, interleukin-10, and transforming growth factor-beta1 genes in acute hepatic allograft rejection.

BACKGROUND: The occurrence of acute rejection in orthotopic liver transplantation is unpredictable. The role of cytokines in the process of rejection is not entirely clear. We investigated polymorphisms in the genes encoding tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, and transforming growth factor (TGF)-beta1, which affect the amount of cytokine produced in vitro, in a liver transplant population to determine any association with acute rejection. METHOD: DNA was extracted from whole blood of liver transplant patients. After amplification with polymerase chain reactions, the polymorphisms at TNF-alpha -308, IL-10 -1082, and TGF-beta1 +869 and +915 were determined using sequence-specific oligonucleotide probes. Acute cellular rejection was a clinical and histological diagnosis. RESULTS: Acute cellular rejection requiring treatment occurred in 68 (48%) of 144 patients. Acute cellular rejection was significantly associated with the TNF-alpha -308 A/A genotype (P<0.02). There was no significant association with either IL-10 or TGF-beta1 polymorphisms in acute rejection. CONCLUSION: Patients with a homozygous TNF-alpha -308 genotype A/A are more likely to suffer from acute cellular rejection after liver transplantation.

Polymorphisms in tumour necrosis factor alpha, interleukin-10 and transforming growth factor beta1 genes and end-stage liver disease.

OBJECTIVE: To determine any relationship between polymorphisms in the genes encoding tumour necrosis factor alpha (TNFalpha), interleukin-10 (IL-10) and transforming growth factor beta1 (TGFbeta1) 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 TGFbeta1 +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 auto-immune 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 TGFbeta1. 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 TNFalpha in vitro and may indicate a predisposition to these inflammatory conditions.

The prediction of acute cellular rejection in orthotopic liver transplantation.

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.

The outcome of the first 165 orthotopic liver transplants in Scotland.

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 of de novo haematological malignancy. The outcome of the first 165 transplants in Scotland compares very well with other countries throughout the world.

Acute liver failure: complications and current management.

Acute liver failure often requires input from physicians, anaesthetists and surgeons. Use of artificial liver systems may change the management of this condition and improve the prognosis when there is no liver transplantation. This article looks at the diverse aetiology of acute liver failure, and outlines current management, work with artificial liver systems and new surgical approaches.

The effect of a positive T-lymphocytotoxic crossmatch on hepatic allograft survival and rejection.

The influence of crossmatching in liver transplantation is still controversial, and at present, our unit does not alter management according to the result of standard lymphocytotoxicity testing. This study retrospectively assessed outcome of grafts transplanted in the presence of preformed antidonor cytotoxic antibody. One hundred twelve patients undergoing their first orthotopic liver transplantation had results available (mean follow-up: 18 months). Twelve patients had a positive crossmatch and 100 negative. The 1-year graft survival was 58% in the positive crossmatch group, compared with 81% in the negative crossmatch group (P = .02). The 1-year patient survival was 83% in the positive crossmatch group compared with 90% in the negative group (P = .41). Acute cellular rejection occurred in 6 of 7 (86%) grafts surviving more than 7 days in the positive crossmatch group compared with 46 of 88 (52%) grafts in the negative group (P = .09). However, episodes of further acute cellular rejection requiring treatment occurred in 4 of the 6 grafts in the positive crossmatch group but in only 4 of the 46 grafts with a negative crossmatch (P = .0006). The authors conclude that evidence exists in our population that preformed antidonor antibodies adversely affect the outcome of hepatic allografts but not patient survival.

Ten year follow up of patients referred for coronary artery bypass grafting from a single district general hospital.

OBJECTIVE: To determine the status of patients 10 years after referral for coronary artery bypass graft (CABG) surgery. DESIGN: Retrospective analysis of case notes from all patients referred between 1 April 1981 and 31 March 1985. Full information gathered from hospital notes, GP records, and Registrar General for Scotland. SETTING: District General Hospital, West Lothian, Scotland. PATIENTS: 102 patients referred for CABG during study period. Cardiac surgery was undertaken in Brompton Hospital, London, Royal Infirmary, Edinburgh, and Western Infirmary, Glasgow. RESULTS: At 10 years after operation 32 patients had died (27 cardiac, five non-cardiac causes). Full data were not available for five patients. Of the 65 remaining patients 24 had no angina, 13 had had a repeat procedure (CABG or angioplasty), and 28 had angina. CONCLUSIONS: Long term benefits of CABG surgery is disappointing. Further steps are required to reduce progression of disease in this population.

Monoclonal antibodies as probes for detecting lipopolysaccharide expression on Escherichia coli from different growth conditions.

Monoclonal antibody (mAb) probes were used to investigate the expression of lipopolysaccharide (LPS) on four Escherichia coli strains, grown under a variety of conditions in batch culture which mimicked some of the in vivo environmental conditions of an infected host. Techniques of silver staining, immunoblotting, whole cell ELISA and flow cytometry were all used to monitor the expression of LPS on the bacteria and the binding of the anti-LPS mAbs. Growth in heat-inactivated sheep serum and magnesium-depleted conditions demonstrated increased expression of LPS core and subsequent increased binding of anti-core mAbs. Magnesium-depleted conditions also resulted in decreased production of O-polysaccharide material. Iron-depleted bacteria showed only minor changes in LPS expression, although increased binding of anti-core mAbs was observed. Nitrogen-deficient/high-carbon conditions, chosen to promote capsule production, resulted in increased expression of O-polysaccharide and decreased binding of anti-core mAbs.