Comparison of liver transplantation outcomes from adult split liver and circulatory death donors.

BACKGROUND: Adult whole-organ donation after circulatory death (DCD) and 'split' extended right lobe donation after brain death (ERL-DBD) liver transplants are considered marginal, but direct comparison of outcomes has rarely been performed. Such a comparison may rationalize the use of DCD livers, which varies widely between UK centres. METHODS: Outcomes for adult ERL-DBD livers and 'controlled' DCD liver transplantations performed at the Cambridge Transplant Centre between January 2004 and December 2010 were compared retrospectively. RESULTS: None of the 32 patients in the DCD cohort suffered early graft failure, compared with five of 17 in the ERL-DBD cohort. Reasons for graft failure were hepatic artery thrombosis (3), progressive cholestasis (1) and small-for-size syndrome (1). Early allograft dysfunction occurred in a further five patients in each group. In the DCD group, ischaemic cholangiopathy developed in six patients, resulting in graft failure within the first year in two; the others remained stable. The incidence of biliary anastomotic complications was similar in both groups. Kaplan-Meier survival analysis confirmed superior graft survival in the DCD liver group (93 per cent at 3 years versus 71 per cent in the ERL-DBD cohort; P = 0·047), comparable to that of contemporaneous whole DBD liver transplants (93 per cent at 3 years). Patient survival was similar in all groups. CONCLUSION: Graft outcomes of DCD liver transplants were better than those of ERL-DBD liver transplants. Redefining DCD liver criteria and refining donor-recipient selection for ERL-DBD transplants should be further explored.

Unusual case of abdominal pain following liver transplant: causality or casualty?

This is an unusual case of chronic abdominal pain following two liver transplants with at least three potential causes: traumatic neuroma, intussusception of the small bowel of the Roux loop and biliary cast. Surgical removal of the latter two factors led to resolution of the pain. The management of the clinical case is discussed.

Cystic fibrosis liver disease: to transplant or not to transplant?

Biliary cirrhosis complicates some adults with cystic fibrosis (CF) and may require transplantation. Cardio-respiratory disease severity varies such that patients may require liver transplantation, heart/lung/liver (triple) grafts or may be too ill for any procedure. A 15-year experience of adults with CF-related liver disease referred for liver transplantation is presented with patient survival as outcome. Twelve patients were listed for triple grafting. Four died of respiratory disease after prolonged waits (4-171 weeks). Eight underwent transplantation (median wait 62 weeks); 5-year actuarial survival was 37.5%. Four died perioperatively; only one is alive at 8-years. Eighteen patients underwent liver transplant alone (median wait 7 weeks); 1- and 5-year actuarial survival rates were 100% and 69%. Three long-term survivors required further organ replacement (two heart/lung and one renal). Two others were turned down for heart/lung transplantation and four have significant renal impairment. Results for triple grafting were poor with unacceptable waiting times. Results for liver transplant alone were satisfactory, with acceptable waiting times and survival. However, further grafts were required and renal impairment was frequent. The policy of early liver transplantation for adults with CF with a view to subsequent heart/lung or renal transplantation needs assessment in the context of long-term outcome.

Survival after liver transplantation in the United Kingdom and Ireland compared with the United States.

BACKGROUND AND OBJECTIVE: Surgical mortality in the US is widely perceived to be superior to that in the UK. However, previous comparisons of surgical outcome in the two countries have often failed to take sufficient account of case-mix or examine long-term outcome. The standardised nature of liver transplantation practice makes it uniquely placed for undertaking reliable international comparisons of surgical outcome. The objective of this study is to undertake a risk-adjusted disease-specific comparison of both short- and long-term survival of liver transplant recipients in the UK and Ireland with that in the US. METHODS: A multicentre cohort study using two high quality national databases including all adults who underwent a first single organ liver transplant in the UK and Ireland (n = 5925) and the US (n = 41,866) between March 1994 and March 2005. The main outcome measures were post-transplant mortality during the first 90 days, 90 days to 1 year and beyond the first year, adjusted for recipient and donor characteristics. RESULTS: Risk-adjusted mortality in the UK and Ireland was generally higher than in the US during the first 90 days (HR 1.17; 95% CI 1.07 to 1.29), both for patients transplanted for acute liver failure (HR 1.27; 95% CI 1.01 to 1.60) and those transplanted for chronic liver disease (HR 1.18; 95% CI 1.07 to 1.31). Between 90 days and 1 year post-transplantation, no statistically significant differences in overall risk-adjusted mortality were noted between the two cohorts. Survivors of the first post-transplant year in the UK and Ireland had lower overall risk-adjusted mortality than those transplanted in the US (HR 0.88; 95% CI 0.81 to 0.96). This difference was observed among patients transplanted for chronic liver disease (HR 0.88; 95% CI 0.81 to 0.96), but not those transplanted for acute liver failure (HR 1.02; 95% CI 0.70 to 1.50). CONCLUSIONS: Whilst risk-adjusted mortality is higher in the UK and Ireland during the first 90 days following liver transplantation, it is higher in the US among those liver transplant recipients who survived the first post-transplant year. Our results are consistent with the notion that the US has superior acute perioperative care whereas the UK appears to provide better quality chronic care following liver transplantation surgery.

Predicting progressive hepatic fibrosis stage on subsequent liver biopsy in chronic hepatitis C virus infection.

Retrospective cross-sectional studies indicate that 20% with chronic hepatitis C virus (HCV) infection become cirrhotic within 20 years. Known risk factors for advanced hepatic fibrosis include age at time of infection, male sex, excess alcohol consumption and cytokine polymorphisms. Prospective study to assess and identify factors predictive of change in hepatic fibrosis stage in chronic HCV infection by interval protocol liver biopsy was performed. One hundred and five patients with paired liver biopsy specimens separated by a mean 41 months were recruited from a cohort of 823 HCV carriers. Five per cent developed worsening hepatic fibrosis by more than two stages. In 43% there was no change in fibrosis stage. Excessive alcohol intake currently (P = 0.037) or previously (P = 0.07) predicted progression. In contrast, always having a normal alanine transaminase (P = 0.038) and always being negative in serum for HCV RNA (P =0.067) predicted no progression. Three models were developed to predict outcome. Progressive fibrosis was predicted by baseline fibrosis (P = 0.018), steatosis (P = 0.02) and age (P = 0.017). The rate of progressive fibrosis was predicted by baseline fibrosis (P = 0.0002), steatosis (P =0.039) and lobular inflammation (P = 0.09). Fibrosis stage on the second biopsy was predicted by baseline fibrosis alone (P = 0.01). The rate of progression varies widely. Alcohol misuse is an important co-factor. Progressive fibrosis can be predicted at first liver biopsy, where baseline fibrosis is most critical, allowing targeted therapy for those with early disease and a significant risk of progression.

Adult small intestinal transplantation in England and Wales.

BACKGROUND: In 1996 two transplantation centres in the UK were commissioned by the National Specialist Commissioning Advisory Group for England and Wales to assess small intestinal transplantation in adults. The joint experience of the two centres is presented. METHODS: Patients with irreversible small intestinal failure and complications of parenteral nutrition, and those with abdominal disease requiring extensive visceral resection, were assessed as candidates and where appropriate listed for surgery. RESULTS: Thirty-six patients were assessed for small intestinal transplantation and, of these, 14 underwent surgery. Twelve patients survived the transplantation procedure. Of these, seven patients were alive at 1 year, five at 3 years and three at 5 years. Three patients remain alive. Patient and graft survival improved with experience; the 1-year survival rate improved in the last 4 years of this experience from 43 to 57 per cent, and the 3-year survival rate from 29 to 43 per cent. CONCLUSION: Small intestinal transplantation is associated with a high mortality rate but may benefit carefully selected patients in whom conservative management is likely to carry a greater mortality rate.

Hyperuricemia, gout, and renal function after liver transplantation.

BACKGROUND: Hyperuricemia is a recognized complication of renal and cardiac transplantation, but the development of hyperuricemia and gout following liver transplantation have received less attention. We have retrospectively assessed the prevalence of hyperuricemia in 134 consecutive liver transplant recipients. RESULTS: Forty-seven percent of the liver transplant recipients studied had hyperuricemia. Serum creatinine was higher in hyperuricemic than in nonhyperuricemic patients. Peak uric acid correlated significantly with corresponding serum creatinine (rs=0.694). Only 6% developed gout. All the patients with gout and 10 hyperuricemic patients with renal impairment but without gout were treated with allopurinol. Over a median period of 3 months, mean serum creatinine fell from 177 micromol/l to 160 micromol/l (P=0.01), without change in type or dose of immuno-suppression. CONCLUSIONS: There is an important association between liver transplantation and hyperuricemia. Treatment with allopurinol results in a significant reduction in serum creatinine in patients with gout and in those with hyperuricemia and renal impairment.

Sirolimus: a potent new immunosuppressant for liver transplantation.

BACKGROUND: Sirolimus (rapamycin) is a new immunosuppressant that appears to be synergistic with cyclosporine in kidney transplantation, but with a different side-effect profile. This pilot study evaluated sirolimus in liver transplantation. METHODS: Patients undergoing orthotopic liver transplantation for primary tumors (8), and later for nonmalignant disease (7), received one of three sirolimus-based immunosuppressive regimens. Protocol A comprised sirolimus, microemulsion cyclosporine (target whole blood concentration: 100 ng/ml), and prednisolone; protocol B omitted prednisolone; and protocol C was sirolimus alone. By 3 months after transplantation, all patients were receiving sirolimus as monotherapy. RESULTS: Fifteen patients were treated with a follow-up of 117-806 days. Rejection was more common on monotherapy than double therapy, and absent on triple therapy. The drug was generally well tolerated, with only three patients discontinuing sirolimus: one for hyperlipidemia, one for pneumocystis pneumonia, and one for inability to tolerate the taste of the drug. Two patients discontinued cyclosporine early, both as a result of neurological complications; they continued on sirolimus monotherapy. Five patients died; one suffered a cardiac arrest, and four died from sepsis in association with graft-versus-host disease, recurrent tumor, a paralyzed right hemidiaphragm, and primary nonfunction. CONCLUSIONS: Sirolimus combined with cyclosporine provided potent immunosuppression of liver allografts, and sirolimus monotherapy was adequate and well tolerated as maintenance therapy. Side effects of sirolimus over the short period of follow-up were uncommon and reversible with dose reduction or cessation of therapy.

Prospective study comparing the efficacy of prophylactic parenteral antimicrobials, with or without enteral decontamination, in patients with acute liver failure.

The efficacy of prophylactic parenteral antibacterials, with or without selective decontamination of the digestive tract, was compared in patients with acute liver failure (ALF) or severe acetaminophen hepatotoxicity. One hundred eight patients were randomized on admission to receive intravenous ceftazidime and flucloxacillin, plus either oral and enteral decontamination with colistin, tobramycin, and amphotericin B (group 1), or enteral amphotericin B alone (group 2). The two groups were comparable with respect to age, gender, etiology, coma grade on admission, international normalization ratio, presence of renal failure, Acute Physiology and Chronic Health Evaluation II score, and indicators of poor prognosis. Patients were monitored for clinical and microbiological evidence of infection. There were 15 episodes of infection in 10 of 47 patients (21%) in group 1 and 17 episodes in 12 of 61 patients (20%) in group 2. No differences in incidence, site, and causative organisms of infection were observed between the two groups. Overall, the incidence of infection was significantly higher in patients who developed encephalopathy than in those who did not. In patients who on arrival were not encephalopathic, the development of infection was associated with progression to coma. Duration of Liver Intensive Care Unit (LICU) stay was an independent risk factor for the development of infection. Parenteral antibiotics are effective at reducing the risk of infection in patients with ALF; enteral decontamination provided no additional benefit.

Twenty-seven years of liver transplantation at Addenbrooke's Hospital, Cambridge.

Twenty-seven years ago, liver transplantation at Addenbrooke's Hospital was a very experimental procedure. It is now recognized as an accepted mode of treatment for end-stage liver failure. In the coming year, over 600 liver transplants will take place in the United Kingdom. All western European countries now have an active liver transplantation program and more than 17,000 liver transplants have already been performed. As results improve and the procedure becomes more readily and widely accepted, the donor shortage is likely to get worse, and will be only partially met by the introduction of split livers and living-related donors.

Randomised trial of variceal banding ligation versus injection sclerotherapy for bleeding oesophageal varices.

Injection sclerotherapy of bleeding oesophageal varices is undoubtedly beneficial but it is associated with a substantial complication rate, and variceal rebleeding is common during the treatment period before variceal obliteration is achieved. We aimed to find out whether endoscopic variceal banding ligation is safer and more effective. The two methods were compared in a randomised controlled trial of 103 patients (54 assigned to banding ligation, and 49 to injection sclerotherapy) of whom 21 (39%) and 23 (47%), respectively, had active bleeding at index endoscopy. Both treatments were highly effective in controlling active haemorrhage (91% and 92% respectively). Variceal obliteration was not achieved for 22 patients in each group, but among those whose varices were eradicated, banding ligation achieved obliteration more quickly than did sclerotherapy (mean 39 [SD 4] vs 72 [7] days, p = 0.004) and in fewer endoscopy sessions (3.4 [2.2] vs 4.9 [3.5], p = 0.006). Rebleeding was less common in the banding ligation group than in the sclerotherapy group (16 [30%] vs 26 [53%], p < 0.05). There was no difference in outcome between the groups, but 14 sclerotherapy patients were withdrawn from the trial (7 for orthotopic liver transplantation) compared with only 5 (1 for liver transplantation) in the banding ligation group (p < 0.05). Complication rates were similar in the two groups. Variceal banding ligation is a safe and effective technique, which obliterates varices more quickly and with a lower rebleeding rate than injection sclerotherapy.

Endoscopic sclerotherapy in the management of gastric variceal haemorrhage.

The value of injection sclerotherapy in the management of active gastric variceal bleeding is unclear. A retrospective study was therefore performed of 46 episodes of acute variceal haemorrhage in 41 patients who were treated by endoscopic sclerotherapy. The site of gastric variceal haemorrhage was the lesser curve (Group 1) in 13, within a hiatus hernia (Group 2) in six, and fundal with or without associated oesophageal varices (Type 3) in 22 cases. Haemostasis was achieved by sclerotherapy in 54%, 71.4% and 26%, respectively. After additional measures including balloon tamponade or surgery 85% of the Group 1 cases had stopped bleeding significantly more frequently than was observed in Group 3 (44.4%). More patients in Group 3 died due to uncontrolled bleeding (41%) than in Group I (7.7%). Hospital mortality depended on the severity of the liver disease with 15% of Child's grade A and 56% of grade C cases dying. It is concluded that endoscopic sclerotherapy of gastric varices should be reserved only for lesser curve or hiatal varices and that early surgery (or sclerotherapy using tissue adhesive) be considered for variceal haemorrhage originating from fundal varices.

Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure.

BACKGROUND: When administered early after an overdose of acetaminophen, intravenous acetylcysteine prevents hepatic necrosis by replenishing reduced stores of glutathione. How acetylcysteine improves the survival of patients with established liver damage induced by acetaminophen, however, is unknown. This study was undertaken to determine whether the beneficial effect of acetylcysteine under such circumstances could be due to enhancement of oxygen delivery and consumption. METHODS: We studied the effect of acetylcysteine on systemic hemodynamics and oxygen transport in 12 patients with acetaminophen-induced fulminant hepatic failure and 8 patients with acute liver failure from other causes. The acetylcysteine was given in a dose of 150 mg per kilogram of body weight in 250 ml of 5 percent dextrose over a period of 15 minutes and then in a dose of 50 mg per kilogram in 500 ml of 5 percent dextrose over a period of 4 hours; measurements were made before treatment began and after 30 minutes of the regimen. RESULTS: In the patients with acetaminophen-induced liver failure, the infusion of acetylcysteine resulted in an increase in mean oxygen delivery from 856 to 975 ml per minute per square meter of body-surface area (P = 0.0036), due to an increase in the cardiac index from 5.6 to 6.7 liters per minute per square meter (P = 0.0021). Mean arterial pressure rose from 88 to 95 mm Hg (P = 0.0054) despite a decrease in systemic vascular resistance from 1296 to 1113 dyn.sec.cm-5 per square meter (P = 0.027). There was an increase in oxygen consumption from 127 to 184 ml per minute per square meter (P = 0.0007) associated with an increase in the oxygen-extraction ratio from 16 to 21 percent (P = 0.022). The effects in the patients with acute liver failure from other causes were similar. CONCLUSIONS: The increase in oxygen delivery and consumption in response to acetylcysteine may account for its beneficial effect on survival in patients with fulminant hepatic failure induced by acetaminophen.

Late onset hepatic failure: clinical, serological and histological features.

The clinical, laboratory and histological features of 47 patients with what is defined as late onset hepatic failure are reviewed. Twenty-five of the patients were female and 22 male with a median age of 45 years. Hepatic dysfunction was severe as evidenced by the prolongation of prothrombin time (median = 32 sec, range = 17 to 120 sec). In only four cases was a viral etiology proven (2 hepatitis B, 2 hepatitis A) although the similarity of the clinical features to patients with fulminant viral hepatitis--apart from the longer period of illness prior to the onset of encephalopathy (median = 9 weeks, range = 8 to 24 weeks)--made non-A, non-B infection a possibility in the remainder. There were also similarities to chronic active hepatitis with low titer antibodies to smooth muscle or antinuclear factor in 17% and elevation of the serum IgG in 49%. Liver biopsy in 5 of 8 survivors more than 1 year after initial presentation showed chronic active hepatitis in three. Lobular inflammatory infiltrate, bridging necrosis and multilobular collapse were the features of the acute stage of illness in both the survivors and fatal cases. The patients given corticosteroids did not have a statistically significant improvement in survival, and overall mortality for the series was 81%. Hepatic transplantation, successfully performed in one patient, would appear to offer the best chance of survival for the majority of these patients.

B1 selective adrenoreceptor blockade for the long term management of variceal bleeding. A prospective randomised trial to compare oral metoprolol with injection sclerotherapy in cirrhosis.

Oral metoprolol, in a dose sufficient to reduce resting pulse rate by 25%, was compared with repeated injection sclerotherapy for the long term management of variceal bleeding. The prospective, randomised study was undertaken in 32 patients with biopsy proven cirrhosis and variceal bleeding who were Grade A or B on a modified Child's classification. In the 15 patients receiving metoprolol, portal pressure showed a mean fall of 3.7 mmHg (17.3 +/- 1.2 to 13.6 +/- 1.2 mmHg, p less than 0.01) after four weeks of continuous therapy, as compared with pretreatment levels. Nine of the 15 patients taking metoprolol had further bleeding (total of 21 episodes) compared with six of 17 in the sclerotherapy group (nine episodes). The risk of bleeding per patient/month of follow up was three times higher in the metoprolol group compared with those treated by sclerotherapy (0.14 and 0.04 respectively, p less than 0.025). Rebleeding in the metoprolol group occurred in six of the patients who had a fall in portal pressure of 10% or more.