Acute renal failure after cadaveric related liver transplantation

Acute renal failure (ARF) is a frequent medical complication after liver transplantation (LT). We analyzed cadaveric related liver transplant recipients who had developed ARF early in the postoperative course. Between January 1982 and August 2003, a total of 67 patients underwent cadaveric related LT. Their mean age was 28.64 years at LT. The 67 recipients had the following indications: biliary atresia (n = 17), Wilson's disease (n = 15), hepatitis B-related liver cirrhosis (n = 14), hepatitis C-related liver cirrhosis (n = 4), primary biliary cirrhosis (n = 4), hepatitis B-related liver cirrhosis with hepatoma (n = 3), hepatitis C-related liver cirrhosis with hepatoma (n = 2), Budd-Chiari syndrome (n = 2), neonatal hepatitis (n = 1), choledochus cyst (n = 1), autoimmune cirrhosis (n = 1), neuroendocrine tumor (n = 1), and hemangioendothelioma (n = 1). Forty-nine patients received cyclosporine (CsA), azathioprine, and steroids and 18, a combination with tacrolimus (FK506). Eight (11.94%) patients developed ARF at a mean time of 17.25 days after LT. The mean peak serum creatinine was 2.24 mg%. Four of these patients had a diagnosis of hepatitis B-related liver cirrhosis; two, hepatitis C-related liver cirrhosis; one, primary biliary cirrhosis; and one, hepatitis B-related liver cirrhosis with hepatoma. The ARF etiology was multifactorial for the majority of patients. Eight ARF patients had a history of liver cirrhosis, which may be a risk factor for intraoperative ARF. ARF treatment included fluid replacement, decreased or altered immunosuppressive agents, avoiding exposure to nephrotoxic drugs, and adjusting antibiotic dosages. The majority of patients returned to normal renal function at 1 to 3 weeks after the diagnosis of ARF. No patient required dialysis and/or experienced a mortality. We conclude that the incidence of ARF is relatively low and with good outcomes. ARF etiology was multifactorial for the majority of patients, but eight patients had a history of liver cirrhosis, which may be a risk factor for intraoperative ARF. We suggest that in the early postoperative period of LT cases diagnosis and treatment of ARF are important.     

Steroid withdrawal in liver transplant recipients

Because of troublesome side effects associated with steroid use, many transplant centers have tried to withdraw steroids from stable, solid organ transplant recipients. The objective of this study was to evaluate the ability to wean liver transplant recipients off steroids, depending on both their primary immunosuppressive regimen and their primary disease state. This was a retrospective, single-center review of steroid weaning in adult orthotopic liver transplant recipients. Based on primary immunosuppression, patients could be weaned off steroids similarly if they were taking cyclosporine or tacrolimus (53.9% vs 61.4%). When triple immunosuppressive regimens were compared with dual regimens, a difference was found in ability to wean patients off steroids (52.4% vs 74.5%, P = .001). When steroid weaning was stratified for primary immunosuppression and primary disease state, patients with autoimmune-mediated diseases (autoimmune hepatitis, sclerosing cholangitis, and primary biliary cirrhosis) were less likely to be weaned if they were receiving cyclosporine-based immunosuppressants (36.8% vs 62.2%, P = .03). In conclusion, it appears that a large number of liver transplant recipients can safely be tapered off steroids.     

Liver Transplantation for Nonviral, Nonmalignant Diseases:Problem of Recurrence

Liver transplantation has evolved rapidly from an experimental treatment to universally accepted therapy for end-stage liver disease. Indications for liver transplantation have expanded with the evolution of the procedure to include metabolic,viral, malignant, and acquired liver failure. As long-term liver transplant recipient follow-up data become available, the development of recurrent liver disease within the transplanted allograft is an increasing dilemma. The value of the transplant procedure must be assessed within the context of survival as well as the potential for recurrent disease and the associated need for re-transplantation. This study represents a compilation of data obtained from adult patients undergoing liver transplantation for nonviral, nonmalignant etiologies at the University of California San Francisco and a comparison of our data with other centers. Between February 1988 and January 1997, 654 liver transplants were performed on 623 patients. From this group, 406 recipients were identified as meeting study inclusion criteria: age above 18 years, and transplantation for a nonmalignant, nonviral etiology of liver failure. Indications for liver transplantation included primary biliary cirrhosis (n = 65), primary sclerosing cholangitis (n = 49), autoimmune hepatitis (n = 37),Budd-Chiari syndrome (n = 7), cryptogenic cirrhosis (n = 88),and alcoholic liver disease (n = 160). Mean follow-up within the diagnostic groups ranged from 4.9 to 5.6 years. Evaluation of clinical,immunosuppressive, and pathologic data for each diagnostic group was performed to determine the incidence, time to recurrence, clinical presentation, and sequelae of disease recurrence.     

Long-term outcome of immunosuppression withdrawal after liver transplantation

Eighteen liver transplant recipients were followed up for 10 years after a trial of immunosuppression withdrawal. Three groups were identified according to the early outcome of complete (group A, n = 5), partial (group B, n = 9), and unsuccessful (group C, n = 4) withdrawal of immunosuppression. The indications for liver transplantation (LT) (August 1983-December 1988) were as follows: primary biliary cirrhosis (n = 3), primary sclerosing cholangitis (n = 3), Budd-Chiari syndrome (n = 3), acute liver failure (n = 3), hepatitis C virus (HCV) cirrhosis (n = 1), HCV and autoimmune hepatitis (n = 1), HCV and alcohol-related cirrhosis (n = 1), HCV and hepatocellular carcinoma (HCC) (n = 1), cystic fibrosis (n = 1), and liver metastases from testicular teratoma (n = 1). Immunosuppression was based on cyclosporine. All patients experienced 1 or more complications of prolonged immunosuppression (median, 7 years; range, 5-11). Thirteen patients (72%) are alive at a median interval of 17 years (range, 16-21) after LT. Of the 5 patients in group A, 2 currently have normal graft function with no rejection episodes, and 3 have restarted immunosuppression following late low-grade acute rejection (n = 1), retransplantation for chronic rejection (n = 1), and kidney transplantation (n = 1). Of the 9 patients in group B, 5 died. The deaths were due to ruptured arterial pseudoaneurysm following retransplantation, HCC recurrence, cardiac failure, renal failure, and posttransplant lymphoma at 5, 7, 7, 14, and 17 years after LT, respectively. All 4 patients in group C are alive on a full immunosuppressive regimen. Long-term follow-up of 18 LT recipients withdrawn from immunosuppression has shown that at a median of 17 years 10% of patients remain off all immunosuppression.     

Cirrhosis after orthotopic liver transplantation in the absence of primary disease recurrence.

Liver allograft cirrhosis is a relatively uncommon complication of liver transplantation. Most cases can be attributed to disease recurrence, particularly recurrent hepatitis C. Little is known about the frequency, etiology, and natural history of liver allograft cirrhosis occurring without evidence of recurrent disease. The aim of the present study was to review the clinicopathological features in this group of patients. We retrospectively reviewed data from all adult patients who were transplanted between 1982 and 2002 and survived >12 months after orthotopic liver transplantation (n = 1,287). Cases of histologically proven cirrhosis were identified from histopathological data entered into the Liver Unit Database. A total of 48 patients (3.7%) developed cirrhosis. In 29 of them, cirrhosis could be attributed to recurrent disease (hepatitis C, 11; hepatitis B, 4; autoimmune hepatitis, 4; primary biliary cirrhosis, 2; primary sclerosing cholangitis, 3; nonalcoholic steatohepatitis, 4; alcoholic liver disease, 1). In 9 of the 19 patients without evidence of disease recurrence, another cause of cirrhosis could be identified (de novo autoimmune hepatitis, 4; biliary complications, 4; acquired hepatitis B, 1). In the remaining 10 cases, the cause of cirrhosis remained unknown; their previous biopsies had shown features of chronic hepatitis of uncertain etiology. Three patients in this group died, and the remaining 7 are alive with good graft function 3-12 years after cirrhosis was first diagnosed. The prevalence of "cryptogenic" posttransplant cirrhosis was significantly higher in patients initially transplanted for fulminant seronegative hepatitis (6%) than in those transplanted for other diseases (0.3%). In conclusion, posttransplant cirrhosis without disease recurrence is uncommon, but it is more frequent in patients transplanted for fulminant seronegative hepatitis. Chronic hepatitis is the most frequent underlying pathological process in cases where the cause of cirrhosis remains uncertain.     

Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States

Because of the ongoing epidemics of obesity and diabetes, nonalcoholic steatohepatitis (NASH) may become a leading indication for liver transplantation. There are concerns about the posttransplant survival of patients with NASH because of associated cardiovascular and metabolic risk factors. We aimed to determine recent trends in the proportion of patients undergoing transplantation for NASH-related cirrhosis in the United States and to estimate their posttransplant survival. We used data provided by the United Network for Organ Sharing for first-time adult cadaveric liver transplants performed in the United States between January 1, 1997 and October 31, 2010 (n = 53,738). The proportion of liver transplants performed for NASH-related cirrhosis increased dramatically from 1.2% in 1997-2003 to 7.4% in 2010 when NASH was the fourth most common indication for transplantation. The posttransplant survival of patients with NASH (n = 1810) at 1 (87.6%), 3 (82.2%), and 5 years (76.7%) was superior to the survival of patients with hepatocellular carcinoma, hepatitis C virus, alcoholic liver disease, acute hepatic necrosis, hemochromatosis, or cryptogenic liver disease and was inferior to the survival of only 4 groups of patients (those with primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, or hepatitis B virus). In conclusion, NASH-related cirrhosis is increasing rapidly as an indication for liver transplantation in the United States and is associated with excellent posttransplant survival.     

Morbidity and mortality in liver retransplantation

INTRODUCTION: The incidence of orthotopic liver retransplantation (re-OLT) ranges from 6% to 11%. The most frequent causes of early re-OLT are allograft failure, uncontrolled acute rejection, and vascular complications. MATERIALS AND METHODS: A retrospective study of 512 orthotopic liver transplants (OLTs) in 482 patients over 15 years. RESULTS: The incidence of re-OLT was 6.6%, with a higher percentage of men requiring re-OLT than first-time OLT (75.0% vs 63.0%, P < .05). The reasons for re-OLT were thrombosis 21.7%, aneurysm 6.5%, stenosis 3.2%, primary nonfunction (PNF) 21.7%, and chronic rejection or recurrence of the initial disease 40.4%. Complications included PNF (22.0%), acute renal failure (65.6%), postoperative infection (87.5%), and adult respiratory distress syndrome (9.4%; P < .05). No differences were seen in the incidence of septicemia or postoperative hemorrhage. The average survival was much lower in re-OLT (21.8 days) compared with OLT (194.5 days; P < .05). The mortality rates in re-OLT were 100% for primary biliary cirrhosis, 85.7% for HCV, 50% for alcoholic cirrhosis, and 20% for HBV. A direct association between the Model for End-stage Liver Disease (MELD) score and the number of complications was present. DISCUSSION: There was a greater requirement for re-OLT in men and those patients transplanted due to hepatitis B virus cirrhosis and fulminant hepatitis (P < .05). The re-OLT patients had no greater incidence of sepsis compared with the OLT patients, although they did have a greater incidence of primary graft dysfunction, acute renal failure, adult respiratory distress syndrome, and postoperative infection (P < .05). The MELD was a good parameter for predicting graft evolution. Re-OLT in patients with primary biliary cirrhosis and hepatitis C virus was associated with a high degree of mortality.     

Orthotopic liver transplantation at Groote Schuur Hospital.

We present data on 10 patients (5 men and 5 women, aged 21-56 yrs) with end-stage liver disease or tumour who underwent orthotopic liver transplantation at Groote Schuur Hospital between October 1988 and June 1991. Standard surgical techniques were used for procuring the donor liver, the recipient hepatectomy and the implantation of the liver. The venovenous bypass method was used in all but 2 patients. Postoperative immunosuppression was usually achieved with cyclosporin, azathioprine and low-dose steroids. Six patients were treated with prophylactic OKT3. Rejection episodes were treated with bolus doses of intravenous steroids. The indications for liver transplantation included chronic active hepatitis progressing to cirrhosis (5), biliary cirrhosis in association with inflammatory bowel disease (1), sclerosing cholangitis (2), alpha 1-antitrypsin deficiency (1), and tumour (1). All patients with chronic liver disease had experienced at least one complication, examples of which included encephalopathy, bacterial peritonitis, ascites, variceal bleeding and septicaemia. Serious postoperative complications included acute rejection of the transplanted liver, renal and liver failure that responded to intensive care support and medical management. One patient died on the 11th postoperative day with complications of bleeding oesophageal ulcer, shock and fungaemia. The remaining patients are alive and well 1-31 months after transplantation.     

Results of liver transplantation according to indications for orthotopic liver transplantation

OBJECTIVE: This study assessed the results of liver transplantation in patients with a variety of different indications. METHODS: From 1989 to April 2003, 209 orthotopic liver transplantations (OLTx) were performed on 196 patients, including 178 cases. The diagnoses were: PBC (n = 34); PSC (n = 13); elective postinflammatory cirrhosis in the course of hepatitis C (n = 29); hepatitis B (n = 16); postalcoholic cirrhosis (n = 23), autoimmune cirrhosis (n = 11); Wilson's disease (n = 6); cirrhosis of unknown etiology (n = 10); secondary biliary cirrhosis (n = 5); Budd-Chiari syndrome (n = 6); and benign liver neoplasms (n = 7). RESULTS: The 3-year survival rate in the group of patients transplanted electively was 74.1%. In other groups it was: PBC, 91.4%; PSC, 69.2%; hepatitis C, 69.6%; hepatitis B, 55.5%; postalcoholic cirrhosis, 80%; autoimmune cirrhosis, 81.8%; Wilson's disease, 57.1%; secondary biliary cirrhosis, 40%; Budd-Chiari syndrome, 66.6%; hemochromatosis, 100%; benign neoplasms of the liver, 87.5%; and liver cysts, 100%. CONCLUSIONS: Results of liver transplantation were closely related to the urgency of the procedure. Better results were achieved in patients operated upon routinely compared with in those operated upon emergently (74.1% vs 50%). The best results of liver transplantation were achieved in patients transplanted on a routine basis with a diagnosis of PBC (91.4%), autoimmunologic cirrhosis (81.1%), postalcoholic cirrhosis (80%), or hemochoromatosis (100%). Patients with liver insufficiency due to hepatitis B and Wilson's disease have an increased risk of graft destruction, and the rate of survival in these patients is significantly lower than in other patients.     

Liver transplantation for hepatocellular carcinoma in cirrhotic patients.

BACKGROUND: Hepatocellular carcinoma (HCC) in patients with cirrhosis, due to a limited liver reserve, is often deemed unresectable, even at an early stage. METHODS: In order to evaluate the ongoing transplant programme for cirrhotic patients with HCC at Royal Prince Alfred Hospital, the results of liver transplantation (LTx) for HCC were analysed and the patient actuarial survival was compared with that of those LTx patients without malignancy. RESULTS: A total of 441 LTx were performed in 404 patients between January 1986 and April 1998. Twenty-four LTx recipients (22 men; two women) of mean age 49 (15-62) years had HCC. Twenty-one had underlying aetiology for their cirrhosis (hepatitis B: n = 9; hepatitis C: n = 8; hepatitis B and C: n = 1; haemochromatosis: n = 1; autoimmune hepatitis: n = 1; alcoholism: n = 1), while three patients had cryptogenic cirrhosis. Six patients had incidental tumours and another two cases were of the fibrolamellar type. The average tumour size and tumour number were 2.9 (0.4-11.5) cm and 1.3 (1-4), respectively. Operative mortality was 4.2% (1/24). The HCC recurrence appeared in one (4.2%) patient (with a 11.5-cm HCC) who died 18 months after LTx. A further two patients died (one graft failure from recurrent hepatitis C and one from fungal sepsis) during follow-up. The overall 1- and 3-year actuarial patient survival rates were 87% and 76%, respectively, and that of patients with benign causes (n = 369) were 77% and 72% (P = NS). CONCLUSION: With careful patient selection, long-term tumour-free patient survival can be achieved. The results support an active transplant programme for selected HCC.     

Cancers of new appearance in liver transplant recipients: incidence and evolution

OBJECTIVE: To investigate the incidence, time of appearance, treatment, and evolution of tumors appearing in liver transplant recipients at our hospital. MATERIAL AND METHODS: We undertook a retrospective analysis of our series of liver transplants between 1990 and 2005. Patients who died during the immediate postoperative period were excluded. RESULTS: Of the 515 patients, 25 died during the immediate postoperative period and therefore had no occasion to develop neoplasms. Of the remaining 490, 32 developed cancers (6.5%). The average age was 55.4 +/- 7.17 years. The reasons for transplant were alcoholic cirrhosis (n = 15), hepatitis C virus (2), hepatitis B virus (n = 1), alcoholic and viral cirrhosis (n = 7), primary biliary cirrhosis (n = 1), and cryptogenic cirrhosis (n = 1). Four patients developed multiple neoplasms. Most of the tumors were cutaneous: nine basal cell and six squamous cell carcinomas. Other locations were the lung, urothelium, stomach, thyroid, and brain. Eight patients presented metastasis at the time of diagnosis. The average tumor-free period was 3.36 years. Nine patients died as a result of the tumor. DISCUSSION: Patients with a liver transplant have a high risk of developing cancers as a result of the immunosuppression treatment, which is lifelong. Nevertheless, other factors can be involved, such as infection by cytomegalovirus or the original diagnosis leading to transplantation. The risk for developing cancers is significantly greater than in the general population, with a higher tendency to recurrence and later development of second neoplasms.     

Biliodigestive anastomosis in liver transplantation: review of 13 years

Hepaticojejunostomy is a good alternative technique for biliary reconstruction in liver transplantation. Among 517 liver transplants performed between March 1992 and July 2005, 33 involved hepaticojejunostomy, namely, 18 men and 12 women of average age: 44.8 years. The main cause for this technique was retransplant (n = 10), secondary biliary cirrhosis (n = 5), alcoholic cirrhosis (n = 5), HCV cirrhosis (n = 2), primary biliary cirrhosis (n = 1), cryptogenic cirrhosis (n = 1), sclerosing cholangitis (n = 3), fulminant liver failure (n = 1), autoimmune cirrhosis (n = 1), and insulinoma metastasis (n = 1). Choledochojejunostomy was performed for all Roux-en-Y loops, with an average cold ischemia time of 361.16 minutes (180-780). The biliary complications were biliary fistula in four cases (13.3%), including two who required surgery; stenosis of the anastomosis in two cases (6.6%) including one diagnosed by HIDA that resolved with medical treatment and the other, diagnosed by cholangio-MRI, requiring a new hepaticojejunostomy; and biliary peritonitis in three cases (10%), all of whom required surgery. The vascular complications were thrombosis of the hepatic artery (n = 1), which required retransplantation, and pseudoaneurysm of hepatic artery (n = 1). No biliary complications occurred. The 6-month patient survival was 80% and the 6-month graft survival was 77%; no patient died due to biliary complications. Hepaticojejunostomy is a technique with higher morbidity than choledocho-choledochostomy, but it is the best alternative when the latter is not possible.     

肝肾联合移植15例报道

目的探讨肝肾联合移植的适应证和疗效。方法对2001年2月至2003年12月施行肝肾联合移植术的15例患者进行了随访。15例中,乙型肝炎后肝硬化合并肝肾综合征8例、合并尿毒症2例、合并糖尿病肾病1例;多囊肝和多囊肾2例;Caroli病合并多囊肾1例;酒精性肝硬化合并尿毒症1例。对肝肾联合移植患者的手术方式,围手术期并发症,术后急、慢性排斥反应和乙型肝炎复发情况及随访结果进行了分析。结果15例肝肾联合移植术后移植物功能均恢复良好,6个月和1年生存率为100%。1例术前有严重营养不良者,术后给与48d的呼吸机支持后康复。术后创面出血和消化道出血各1例,经非手术治疗后治愈。胆道吻合口狭窄1例,用内镜下球囊扩张术治愈。1例术后2周发生急性移植肝排斥反应,给予激素冲击治疗后得到控制。1例术后30个月时因停用拉米夫定后乙型肝炎复发死于移植肝功能丧失。结论肝肾联合移植是终末期肝病合并慢性肾功能衰竭或肾功能损害的安全有效方法。对乙型肝炎患者术后尽早应用拉米夫定和乙型肝炎病毒免疫球蛋白预防肝炎复发。     

Ten years of liver transplantation at Groote Schuur Hospital.

INTRODUCTION: Liver transplantation has evolved from an experimental procedure to being the treatment of choice for many patients with end-stage liver disease, and is performed on a routine basis in most major centres throughout the world. However, certain situations peculiar to developing countries have a major impact on liver transplant programmes in these countries. We present the results of the liver transplant programme in Cape Town. PATIENTS AND METHODS: All patients undergoing orthotopic liver transplantation at Groote Schuur Hospital and Red Cross War Memorial Children's Hospital were included in this report. Standard surgical techniques were used for procuring the donor liver, the recipient hepatectomy and the subsequent implantation of the liver. All patients received standardised peri-operative management; in particular, the immunosuppressive protocol consisted of cyclosporin, steroids and azathioprine. Since October 1988, 83 patients have undergone 89 orthotopic liver transplants. There were 44 adults and 39 children, the age range being from 6 months to 56 years. The commonest indications for hepatic transplantation in adults included cryptogenic cirrhosis, auto-immune hepatitis and primary sclerosing cholangitis. In children biliary atresia was the commonest cause of liver failure. RESULTS: Of the 81 patients transplanted, 50 are alive and well with follow-up ranging from 2 months to 9.5 years. The cumulative graft survival rate was 72% at 1 year and 61% at 5 years. Six patients have undergone re-transplantation and 4 patients have had combined liver/kidney transplants. De novo hepatitis due to hepatitis B virus (HBV) has occurred in 8 patients following transplantation. Subsequent investigation has shown that 5 of the donors of these livers were hepatitis B core antibody (HBcAb)-positive, while information on the remaining 3 was not available. Tuberculosis (TB) has been a significant problem in 4 patients, with 2 deaths precipitated by anti-TB drug-induced hepatitis. Post-transplant lymphoproliferative disorder was also responsible for significant postoperative morbidity. CONCLUSION: Orthotopic liver transplantation has been established at Groote Schuur Hospital as the treatment of choice for selected patients with chronic end-stage liver disease. However, hepatitis B and TB appear to present a problem. The particularly high prevalence of HBV carrier status in our donor population may necessitate the use of living donors in the future.     

Clinicopathological review of 18 cases of liver allografts lost due to bile duct necrosis

Clinical, radiographic, and pathological features of 18 patients with biliary necrosis in their explanted liver allografts were reviewed. Twelve patients were men and ages ranged from 27 to 72 years. Indications for initial liver transplant (LT) were viral hepatitis (n = 7), steatohepatitic cirrhosis (n = 3), cryptogenic cirrhosis (n = 3), secondary sclerosing cholangitis (n = 2), primary sclerosing cholangitis (n = 1), biliary atresia (n = 1), and nodular regenerative hyperplasia (n = 1). Donor age ranged from 16 to 75 years. Duct-to-duct biliary anastomoses were fashioned in 13 cases; warm and cold ischemia times were not significantly different from general LT population. Seventeen allograft biopsies after recirculation had no significant findings. Post-LT, clinical and radiographic evaluation indicated biliary strictures (n = 7), bile leak (n = 7), intrahepatic abscess (n = 1), and duodenal perforation (n = 1). Radiographic vascular studies suggested hepatic arterial thrombosis or stenosis in 11 cases. Biopsies prior to retransplantation were performed on 17 patients and showed acute rejection (n = 10), biliary outflow impairment (n = 4), normal histology (n = 2), and centrilobular necrosis (n = 1). Retransplantation was performed 14 to 334 days after initial LT. Pathological examination of explants revealed perihilar duct necrosis in all cases, with bacterial colonies (n = 10) and fungal organisms (n = 2). Arterial thrombi were seen in 10 cases, and two had prominent arteriosclerosis. Infarction and centrilobular necrosis were seen in 9 and 13 cases, respectively. Four explants showed features of biliary outflow impairment. Twelve patients were alive 6 to 18 months following retransplantation. We conclude that post-LT biliary necrosis is associated with ischemia, and such a complication is rarely evident in allograft biopsies. Biliary and vascular imaging studies are essential in evaluating patients for this complication.     

Tumor necrosis factor-α promoter polymorphisms and the risk of rejection after liver transplantation: A case control analysis of 210 donor-recipient pairs

After orthotopic liver transplantation (OLT), allograft rejection remains an important problem and is the major reason that immunosuppressive therapy must be administered. Tumor necrosis factor-α (TNF-α) is a proinflammatory mediator that is central to the immune response, and intragraft expression of this cytokine is increased during acute cellular rejection (ACR). Polymorphisms within the TNF promoter have been identified and correlated with alterations in production. The aims of this study were to determine if an individual patient's propensity to develop ACR is related to the presence of these genetic polymorphisms (either alone or in combination) within donor and recipient tissue and to determine if these polymorphisms affect patient survival after OLT. The study group consisted of 210 patients who underwent OLT between 1989 and 1999 with at least 6 months survival, including 42 cases who had evidence of acute cellular rejection (biopsy-proven, elevated enzymes, and response to increased immunosuppression) and were matched 4:1 to controls (n = 168) with similar age, gender, underlying liver disease, date of transplant, and baseline immunosuppression. The underlying liver diseases were hepatisis C virus (HCV)/alcohol (70), HCV alone (50), alcohol (30), primary biliary cirrhosis (15), primary sclerosing cholangitis (15), autoimmune hepatitis/cirrhosis (10), cryptogenic (15), and hepatitis B virus (HBV) (5). DNA was extracted from paraffin-embedded donor and recipient liver tissue (total 420 samples), amplified, and sequenced for TNF single-nucleotide polymorphisms (TNFA-308 A/G and TNFA-238 A/G). We found no differences between the TNF allelic distributions among donors without liver disease (presumably representative of a normal control population) and patients with end-stage liver disease undergoing OLT. Multivariate analysis revealed no association with TNF polymorphisms (within donor or recipient tissue) and rejection risk or patient survival after transplantation. In this large case control analysis of patients undergoing liver transplantation for diverse etiologies, TNF promoter polymorphisms were not independently associated with rejection or survival. (Liver Transpl 2003;9:377-382.)     

Indications for liver transplantation in the cyclosporine era

One hundred seventy orthotopic liver transplants were performed under conventional immunosuppression with azathioprine and steroids with 1- and 5-year survivals of 32.9 per cent and 20.0 per cent, respectively. Since the introduction of cyclosporine-prednisone therapy in March 1980, 313 primary orthotopic liver transplants have been performed. Actuarial survivals at 1 and 5 years have improved to 69.7 per cent and 62.8 per cent, respectively. Biliary atresia is now the most common indication for liver replacement. In adults, primary biliary cirrhosis and sclerosing cholangitis have become more common indications for transplantation, and alcoholic cirrhosis and primary liver malignancy as indications have declined. Early enthusiasm for liver transplantation in patients with hepatic cancer has been tempered by the finding that recurrence is both common and rapid. An increasing number of patients with inborn errors of metabolism originating in the liver are receiving transplants, including patients with Wilson's disease, tyrosinemia, alpha-1-antitrypsin deficiency, glycogen storage disease, familial hypercholesterolemia, and hemochromatosis. Survival in this group of patients has been excellent (74.4 per cent at 1 and 5 years). A hemophiliac who received a transplant for postnecrotic cirrhosis has survived and may have been cured of his hemophilia. About 20 per cent of patients require retransplantation for rejection, technical failure, or primary graft failure. Only four of the patients receiving retransplants under conventional immunosuppression survived beyond 6 months, and all died within 14 months of retransplantation. Sixty-eight patients have received retransplants under cyclosporine-prednisone. Thirty-one patients are surviving, all for at least 1 year. Six of the twelve patients requiring a third transplant are alive 2 to 3 years after the primary operation. An aggressive approach to retransplantation in the patient with a failed graft is justified.     

Distinct enzyme profiles in patients with cryptogenic cirrhosis reflect heterogeneous causes with different outcomes after liver transplantation (OLT): a long-term documentation before and after OLT

BACKGROUND: Sound information is lacking about the clinical presentation of cryptogenic cirrhosis and its outcome after orthotopic liver transplantation (OLT). METHODS: Among 856 patients who have been transplanted at our center, 40 patients had no evidence of any known etiologies and were therefore defined as suffering from cryptogenic cirrhosis. Their median follow-up period before OLT was 78 months (range, 1-264), and after OLT 97 months (range, 1-132). Laboratory and histological data were evaluated according to features being compatible either with a toxic, hepatitic, or cholestatic condition. RESULTS: The clinical and histological findings differed specifically between these three groups. The toxic-like group (GGT 4-18 x upper limit of normal [ULN]) expressed significantly higher IgA levels, had histologically more often fatty liver changes, and risk factors for non-alcoholic steatohepatitis predominated (56% compared with 3% in the other groups, P=0.01). The hepatitic-like group (ALT 2-18 x ULN) showed histologically features of chronic hepatitis or hepatitic cirrhosis, and only among these patients a median International Autoimmune Hepatitis (IAH) score of 13 was found suggesting autoimmune hepatitis (AiH). In the cholestatic group (AP 2-8 x ULN) histology was compatible with a non-toxic inflammatory process but IAH score excluded AiH in all. After OLT, actuarial graft and patients survival was 90% at 5 years. Mild or moderate graft hepatitis occurred in 9 patients (23%) and was significantly associated with a pre-OLT IAH score >or= 10 (P =0.008). CONCLUSIONS: This study provides arguments that cryptogenic cirrhosis is a heterogeneous disease in which autoimmune mechanisms might be predominately involved and being responsible for recurrence of chronic liver disease observed in some instances after OLT.     

Immunosuppression withdrawal after auxiliary liver transplantation for acute liver failure

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.