Role Of Liver Transplantation Research Articles

Role of liver transplantation in management of hepatocellular carcinoma

Role of liver transplantation in management of hepatocellular carcinoma

The role of liver transplantation in cystic fibrosis re-examined

The role of liver transplantation in cystic fibrosis re-examined

Basic concepts in transplant immunology

Subsequently,spontaneousliverallograftacceptancewasalsoobservedintransplants done in several allogeneic rat strain combina-tions and most allogeneic mouse strain combinations.Moreover, other experimental studies in rodents demon-strated that allogeneic liver transplantation providesimmune“protection”againstsubsequentcardiac,kidney,pancreas, islet, and skin grafts from the same donor.

Successful living-related liver transplantation for familial hypercholesterolemia in the Middle East

Familial hypercholesterolemia (FH) is an autosomal dominant inherited metabolic disorder resulting in advanced vascular atherosclerosis and premature death, primarily from coronary artery disease. The primary defect is a mutation in the gene encoding for the plasma LDL receptor located on the short arm of chromosome 19. Liver transplantation is currently the most effective method of treating this disorder. Living-related liver transplantation (LRLT) has become an excellent modality for treating children, including those with inherited metabolic diseases. In this paper, we describe the first report of a LRLT for familial hypercholesterolemia and review FH and the role of liver transplantation.

Living donor liver transplantation for hepatocellular carcinoma

The incidence of hepatocellular carcinoma (HCC) is increasing at an alarming rate in the United States, such that HCC has become an important indication for liver transplantation. The role of liver transplantation in patients with HCC has evolved over the past 2 decades, and transplantation has become one of the few curative treatment modalities for patients with HCC, especially in selected patients with favorable tumors. The advent of living donor liver transplantation for adult recipients provides another therapeutic venue, in particular for patients with HCC who are disadvantaged by current allocation algorithms for grafts from deceased donors. Living donor transplantation may limit the waiting time and, as a result, may decrease the progression of disease so that intuitively the recurrence rate should be lower than for recipients who wait for an organ from a deceased donor. There are limited data on the efficacy of living donor liver transplantation in the setting of HCC. Based on a limited cohort of patients undergoing transplantation for HCC at Northwestern University Medical Center, a higher recurrence rate, stage for stage, was found in recipients whose transplants were accelerated ("fast-tracked") by performing a living donor transplant, especially in the era in which patients with HCC were disadvantaged by the allocation algorithm. Clearly, the role of living donor liver transplantation in management of patients with HCC requires prospective direct analysis of both recurrence and dropout rates in comparable patient cohorts with HCC undergoing either deceased or living donor liver transplantation.

The role of liver transplantation in urea cycle disorders

Liver transplantation has an important role in the management of patients with urea cycle disorders, particularly those with severe variants, progressive liver disease, and some patients who have proved very difficult to control with conventional therapy. As a result of technical advances in liver transplantation, the outlook, both morbidity and mortality, is better and continues to improve. Patients can almost always have a normal diet and the quality of life for survivors is generally excellent.

Role of liver transplantation in the management of metastatic neuroendocrine tumors

Introduction In the majority of patients transplanted for unresectable liver metastases, long-term results are disappointing because of early tumor recurrence. Due to its biologically less aggressive nature, neuroendocrine metastases (NM) may represent a good indication for liver transplantation (LT). Patients and methods Between January 1996 and May 2000, five patients with NM were transplanted. The primary tumors were located in the pancreas ( n = 4) and the small bowel ( n = 1). In three cases there were symptoms related to hormone production: two carcinoids, and one gastrinoma. The management of primary tumors was sequential in three patients with the tumor being resected before LT (one Whipple procedure and two left pancreatectomies). In two patients the resections of the primary tumors and the LT were simultaneous namely one bowel resection and one left pancreatectomy All patients were treated with chemotherapy. Results Two patients developed recurrent disease succumbing at 15 months (nonfunctioning NE pancreatic head tumor) and 17 months (carcinoid of the pancreatic tail) post-LT. Another patient died at 3 months post-LT due to technical complications. The other two patients are alive and free of recurrence. Conclusion Despite the promising results obtained with LT for NM, our experience indi- cates that patients must be carefully selected. Perhaps the use of more aggressive chemotherapeutic protocols combined with an individualized approach will improve the results.

Role of Liver Transplantation in the Management of Hepatocellular Carcinoma

The treatment options for hepatocellular carcinoma (HCC) are liver resection, liver transplantation, or local ablation (e.g., percutaneous ethanol injection, cryosurgery, radio-frequency ablation, and chemoembolization). Most patients are not eligible for curative resection because of the location of the tumor or the severity of liver disease. For many of these patients, liver transplantation remains the best curative option. Because of the shortage of donor organs, much of the recent effort has been aimed at patient selection. In this review, the authors address outcomes after liver transplantation for HCC, the role of selection criteria as a predictor of mortality and recurrence, and the emerging role of living donor liver transplantation and chemoembolization.

Orthotopic liver transplantation for unresectable hepatoblastoma.

The outcome of treatment for advanced hepatoblastoma has recently improved after the introduction of preoperative or pre- and postoperative cisplatin-containing chemotherapy combined with complete surgical excision. The role of liver transplantation in a population of patients who have received this regimen has not been clearly defined. Orthotopic liver transplantation (OLT) was performed in 13 children, aged 5 months to 11 years (median 27 months), who were assessed with unresectable hepatoblastoma, and whose pretreatment extent-of-disease was based on radiologic findings of group III (n=11) and group IV (n=2). One child with a multifocal tumor showed pulmonary metastases at presentation, but, according to radiologic studies, the deposits resolved with chemotherapy before liver transplantation. One other child showed exophytic extension of the primary tumor infiltrating the porta hepatis and body of the pancreas. All 13 patients received preoperative chemotherapy to reduce the size of the primary tumor(s) and to treat metastatic spread. Twelve children underwent elective OLT; all are alive and show normal graft function at a mean follow-up of 33 months (range 1-108). One child shows evidence of recurrent disease in the form of pulmonary metastases. One child underwent emergency OLT for acute liver failure after (incomplete) extended right hepatectomy and died from respiratory failure, with no evidence of recurrent tumor 3 weeks posttransplant. Liver transplantation is an effective treatment for unresectable unifocal or multifocal hepatoblastoma confined to the liver. A multidisciplinary approach to the management of hepatoblastoma, with thoughtful collaboration between pediatric oncologists, hepatologists, and liver surgeons, is essential.

Reperfusion injury associated with portal venous and hepatic arterial perfusion in liver transplantation.

Although reperfusion injury in organ transplantation is presently well established, its exact role in liver transplantation still has to be defined. The aim of this part of the study was to document the reperfusion injury associated with porcine liver transplantation and to evaluate the different components of the reperfusion injury associated with arterial and portal reperfusion. Large white X Landrace pigs were randomized into two groups: group 1, initial portal reperfusion, and group 2, initial arterial reperfusion. Several indicators of reperfusion injury, endothelial cell function, and hepatocellular damage were assessed. Early histopathological findings in biopsy specimens can predict poor graft outcome, therefore histological findings of the liver biopsies after liver transplantation were also studied. Malondialdehyde concentrations were lower and vitamin A concentrations were higher in the animals subjected to initial portal reperfusion. Serum amino aspartate transferase and serum hyaluronic acid concentrations were higher in the animals subjected to initial portal reperfusion. Histological results showed that hepatocyte vacuolization, neutrophil infiltration, single hepatocyte necrosis, and group cell necrosis of the hepatocytes were all significantly reduced in group 2 compared to group 1. Results of this study indicate that the major part of reperfusion injury is constituted during the portal venous reperfusion and that this injury can be, at least partially, attenuated by initial arterial reperfusion.

Liver transplantation for cholangiocellular carcinoma: analysis of a single-center experience and review of the literature.

Cholangiocellular carcinoma (CCC) is a biliary malignancy that frequently presents in advanced unresectable stages. The role of liver transplantation (LT) as a surgical modality is unclear. The goal of this study is to evaluate outcomes of patients with CCC undergoing LT. A retrospective analysis of all patients undergoing LT was undertaken. Only those patients with the pathological diagnosis of CCC were included on the study. Patients were divided into two groups based on primary tumor location: extrahepatic (EH)-CCC and intrahepatic (IH)-CCC. The Kaplan-Meier method was used to calculate overall and recurrence-free survival. Log-rank analysis was used to determine the significance of prognostic variables. Twenty-five patients were identified: 9 patients with EH-CCC (5 patients, Klatskin-type; 2 patients, the middle third; and 2 patients, the distal third) and 16 patients with IH-CCC. Mean age was 47.1 +/- 10.6 years. There were 14 men and 11 women. Tumor stage was local (stages I and II; n = 9) or advanced (stages III and IV; n = 16). Overall and disease-free survival rates were 71% and 67% at 1 year and 35% and 32% at 3 years, respectively. Analysis of variables showed statistically significant improved outcomes (P < .05) for the absence of contiguous organ invasion at LT, small tumor size, and single tumor foci. This study indicates that early survival after LT for CCC is acceptable. Three-year disease-free survival is achieved in approximately 30% of patients. These outcomes can be improved by applying strict selection criteria based on prognostic variables identified in this study.

Congenital absence of the portal vein and role of liver transplantation in children

Background/Purpose: Congenital absence of the portal vein (CAPV) is a subtype of congenital portosystemic shunt, which can cause a broad spectrum of clinical manifestations. The authors report on 4 patients with CAPV including a boy with CAPV-associated encephalopathy, which was resolved effectively by liver transplantation (LT). Methods: The case records of 4 pediatric patients with CAPV who were referred to the author's institution between 1984 and 1999 were reviewed. Results: The patients (3 boys and 1 girl) ranged in age at diagnosis from 0.8 to 14 years. Two patients had growth retardation or disturbed consciousness, and the other 2 had no specific manifestations. Not only high serum levels of bile acids, ammonia, and transaminases but also low plasma levels of branched-chain amino acids were common laboratory findings. The absent portal vein was replaced by a large portosystemic shunt, which connected the splanchnic vein to the inferior vena cava or the left renal vein. Two patients survived without any symptoms, but 1 with growth retardation died of hepatic failure. The other with encephalopathy did not respond to medical therapy and underwent LT, which resolved symptoms and metabolic disorders effectively. Conclusions: Patients with CAPV do not always have a good prognosis. They should be followed up with careful observation of their symptoms, hepatic function, and metabolic abnormalities. LT might be indicated for patients with symptomatic CAPV unresponsive to medical therapy. J Pediatr Surg 36:1026-1031. Copyright © 2001 by W.B. Saunders Company.

Treatment of Hepatic Metastases from Gastroenteropancreatic Neuroendocrine Tumors: Role of Liver Transplantation

The role of liver transplantation in malignancy has been discussed, but controversially, over the past two decades. This is particularly true for hepatic metastases from neuroendocrine tumors, which have a wide variety of primary tumor localizations, morphologic types, functional activities, and clinical presentations. Despite generally slow tumor progression, the prognosis is often unpredictable. Total hepatectomy and liver replacement has been offered primarily to patients with nonresectable metastases and symptomatic disease. The results from retrospective single and multicentric analyses show that most liver recipients experience significant palliation despite tumor recurrence, and in some patients long-term cure can be achieved. The existing data emphasize the importance of proper selection and timing for this approach.

Treatment options for other hepatic malignancies.

1. Resection rates for cholangiocarcinoma (unrelated to primary sclerosing cholangitis) have increased to 54% to 79%, and the subsequent 5-year survival rates are 24% to 31%. 2. Multimodality approaches involving various combinations of chemotherapy, irradiation, and surgery increasingly are being used to treat cholangiocarcinoma. 3. The role of liver transplantation in the management of cholangiocarcinoma is limited by the perception that it is inappropriate to use scarce organs when 5-year survival rates are 25%. 4. Liver transplantation is an important intervention in patients with tumors that remain unresectable after chemotherapy. The role of liver transplantation in patients with extrahepatic disease that responds to chemotherapy is controversial. Careful timing of surgery is required to avoid secondary drug resistance. 5. Liver transplantation has been successfully applied to a range of rare hepatic malignancies, but small numbers preclude strong recommendations on the appropriateness of this practice.

Cancer and liver transplantation

Primary tumors of the liver can be of epithelial, mesenchymal, or mixed origin. Primary malignant epithelial tumors are the most common hepatic tumors. They include hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and a variety of other more rare tumors. HCC has a relentless clinical course. It is characterized by a fulminant evolution, a low rate of resectability, and poor response to nonsurgical therapies. Reports on surgical resection of HCC point toward a complete resectability rate of 3% to 30%. Reported survival ranges from 55% to 90% at 1 year to 10 years and 50% at 5 years. Operative mortality for cirrhotics is between 7% and 25%, although it decreases to less than 3% for noncirrhotics. Multifocal tumors are associated with higher recurrence rates and lower survival times. Tumor size (with 5 cm the usual cutoff point) affects not only survival, but also resectability. Tumor location, well-differentiated histologic grade, presence of a tumor capsule, absence of vascular invasion, and fibrolamellar variety seem to be associated with better outcomes. Tumor size, spread and location, and hepatic functional reserve capacity should be considered before surgery. Ascites and jaundice are unfavorable factors that are associated with adverse outcomes. Favorable prognostic factors include the following: (1) encapsulation of the tumor, (2) negative resection margins, (3) lack of capsular invasion, (4) lack of venous invasion, and. (5) absence of microsatellite lesions. Fibrolamellar carcinoma behaves in a more benevolent fashion in that it has a 50% to 75% resectability rate, with an average survival of 32 to 68 months. HCC treated with liver transplantation may have a recurrence rate sometimes as high as 65%. Actuarial survival rates at 1 and 5 years range from 42% to 71% and 20% to 45%, respectively. Based on results reported by the Klintmalm registry, patient survival is significantly influenced by tumor size greater than 5 cm, vascular invasion, node involvement, and histologic grade. No difference in survival was observed when incidental tumors, fibrolamellar variety, multifocality, and bilobar involvement were considered by univariate analysis. Only histologic grade had a negative impact on overall survival in patients with known tumors. When tumors found incidentally were considered, patient survival was affected by multifocality and age older than 60 years. Postoperative recurrence-free survival was significantly diminished by tumor histologic grade and size greater than 5 cm. Others have found that favorable prognostic factors include incidental finding of tumor during hepatectomy or pathologic analysis, fibrolamellar variety, and small (<5 cm) tumor size. Unfavorable factors include poor differentiation, vascular invasion, extrahepatic metastases, and lymph node involvement (closely linked with pTNM staging). Although reports are somewhat conflicting, cirrhosis seems to affect survival. CCA is classified by its location. We have chosen to subdivide CCA into 2 main groups: central (intrahepatic and hilar) and peripheral. Although there have been numerous reports of surgical treatment of hilar CCA long-term survival has been poor, with few exceptions. One- and 5-year survival rates after resection range from 58% to 79% and 5% to 40%. High perioperative mortality, due to hepatic failure and sepsis, is common. The role of liver transplantation has been debatable in the face of organ shortage. However, categorical denial of liver transplantation for CCA is unjustifiable. An evaluation of multiple studies points toward a surgical resectability rate of 20% to 50% and an operative mortality of 0% to 27%. One-, 3-, and 5-year survival rates were 70% to 100%, 20% to 50%, and 8% to 35%, respectively. Recurrence rates were found to be as high as 75%. HB is the most common malignant liver tumor in children under the age of 5 years. During the last decade, developments in imaging technology, chemotherapy, and surgical techniques have improved the treatment of pediatric liver tumors. Surgery still remains the cornerstone of therapy within a multimodality treatment protocol. Liver transplantation allowed for improved survival in patients with otherwise unresectable disease and should be used, in such instances, as part of a well outlined protocol. Hepatic epithelioid hemangioendothelioma is a low- to intermediate-grade vascular endothelial malignant tumor of unpredictable natural history. No clear-cut association between pretransplantation liver spread and posttransplantation recurrence and survival has been found.

Hepatitis C Infection: Its Sequelaie and Outcomes – State-of-the-Art Workshop, September 24 to 25, 1998

This report summarizes a state-of the- art workshop held in September 1998 on the “Natural History and Outcome of Hepatitis C Infection”. Sixteen Canadian and two internationally renowned hepatologists were invited. A practical classification of HCV infection served as a framework for the meeting. The concepts of modelling of chronic disease, the epidemiology of HCV infection before the introduction of anti-HCV testing, and the outcome of various forms of chronic hepatitis C in adults and children were presented. Lectures on the outcome of HCV cirrhosis, hepatocellular carcinoma, the role of liver transplantation, the influence of host factors on outcome, iron overload in chronic hepatitis C and possible modification of the natural history by antiviral therapy were followed by discussion and consensus statements pertaining to each presentation. “The European Experience in Assessing Chronic Hepatitis C” was presented by Prof G Dusheiko from the United Kingdom, and Prof Leonard Seeff from the National Institutes of Health (United States) presented “The Epidemiology and Outcome of Hepatitis C Infection in the United States and the World”.

Ischemic preconditioning improves liver microcirculation after ischemia/reperfusion

THE ISCHEMIA/REPERFUSION injury plays an important role in liver transplantation and surgery. Oxidative stress after reperfusion results in activation and adherence of leucocytes and platelets. Consequently, alterations in microcirculation develop that lead to impairment of hepatic function. In 22% of the cases extensive reperfusion injury causes severe deterioration of microcirculation leading to primary dysfunction or primary graft failure. A more detailed understanding of pathophysiological mechanisms resulting into treatment possibilities is therefore essential. Ideal treatment makes use of intrinsic protective mechanisms and is offered before damage takes place. Ischemic preconditioning takes that into account. Ischemic preconditioning describes the phenomenon that a brief ischemia and reperfusion, the so-called preclamping, increases the ischemic tolerance of a following ischemic period. It was first described for the heart in 1986 by Murry and since then has been extensively examined. Studies concerning other organs such as muscle and kidney followed. The first study about preclamping in the liver was performed in 1993 by Lloris-Carsi et al. He and others studied different preclamping and reperfusion times, focusing on laboratory liver function tests, energy content of the tissue, histological analyses of cellular integrity, and survival after sublethal stress. The underlying effect of ischemic preconditioning has been of special interest ever since. Some substances such as heat shock protein, adenosine, and nitric oxide (NO) seem to be involved, the exact mechanism has not yet been identified. Thus far, analyses of liver microcirculation after ischemic preconditioning have not been performed. Microcirculatory disturbances can directly be related to organ function and, therefore, to the extent of ischemia/reperfusion injury, respectively, to the benefit of an applied treatment. Therefore, it was the goal of this study to evaluate the effect of ischemic preconditioning on the hepatic microcirculation after warm ischemia/reperfusion by intravital microscopy in rats.

Hepatic dendritic cells: immunobiology and role in liver transplantation.

Traditional investigations of hepatic dendritic cells (DC) have focused on immunohistochemical studies of these cells within normal and pathological liver tissue. The recent availability of reagents for the improved characterization of DC, together with cytokine-based methods for the expansion of liver DC both in vivo and in vitro have begun to provide new insight into the immunobiology of these important antigen-presenting cells. Hepatic DC probably play a key role in the host response to blood-borne pathogens, and in the pathogenesis of infectious and autoimmune liver diseases. They appear to be important in determining the balance between liver transplant tolerance and rejection. Their possible role in oral and portal venous tolerance remains to be defined. In this article, we focus on emerging aspects of hepatic DC immunobiology, with particular reference to liver transplantation.

Detection and characterization of HLA class I molecules in the supernatant of an hepatocarcinoma cell line and of EBV-transformed B cell lines

Human leukocyte antigens (HLA) class I molecules can be detected in “soluble” form in the supernatant of cultured cell lines and in serum and plasma of humans. These “soluble” HLA class I molecules are assumed to play a role in liver transplantation. In order to define the nature and composition of HLA class I molecules found in solution, we studied the HLA class I production of an hepatoma carcinoma cell line (HepG2) and of EBV-transformed B-cell lines. Based on molecular weight (MW) analysis, it was demonstrated that different forms of HLA class I molecules were produced by HepG2 cells and EBV B-cells. Monoclonal antibodies (mAbs) specific for HLA class I alleles were able to recognize the mature 45 kDa form, but failed to interact with the 42 kDa and 39 kDa MW forms of HLA class I. Of these different MW forms of HLA class I molecules the mature 45 kDa product was found predominantly to be associated with subcellular vesicles whereas the alternative MW forms of 42 kDa and 39 kDa exist as truly free entities in supernatants.

LIVER TRANSPLANTATION (LTx) FOR POLYCYSTIC LIVER DISEASE (PLD).

362 Polycystic liver disease (PLD) may provoke massive hepatomegaly, resulting in severe physical-social handicap. Data on the role of liver transplantation (LTx) in the management of PLD are rare and conflictory. Conservative surgery (resection-fenestration) is indicated in large single cysts but its value in small diffuse cysts is questionable. In addition conservative surgery is not devoid of morbidity/mortality. LTx offers the prospect of a fully curative treatment but controversy remains because those patients usually have preserved liver function. Thus, we reviewed our experience with LTx for PLD. 13 adult female patients received a LTx for PLD (small diffuse cysts) between 1990 and 1998. Mean age was 44 yo (36-49). All 13 suffered from combined liver+kidney cystic disease but only I had renal failure and required a combined L and kidney Tx. 12 had preserved kidney function {mean creatinine 1.14 mg/dl (0.91-1.67)} and received a LTx only. Indications for Tx were massive hepatomegaly causing physical handicap (n=13, dyspnea, abdominal pain, vena cava compression, fatigue, dyspepsia), social handicap (n=13), malnutrition (n=2), cholestasis and/or portal hypertension (n=4), associated renal failure (n=1). No marginal liver donors were used. Cold ischemia time was 8.9 hrs (3-15). LTx caused no technical difficulty in 12/13 patients {surgery duration 6.6 hrs (5-8), blood transfusion 7.7 units (0-22)}. One patient who had repeated unsuccessful attempts at liver mass reduction preTx died of massive bleeding and pulmonary emboli. Native liver weight was 5 to 15 kg. PostTx immunosuppression consisted of triple drug therapy with CsA or FK506, imuran and steroid (stopped at 3 mths). All grafts displayed excellent immediate function. Morbidity included biliary stricture (2), revision for bleeding and hepatitis (1), pneumothorax and subphrenic collection (1), bleeding from a tracheostomy (1). There was no post-operative death or graft loss. Both patient and graft survival is 92% (follow-up: 5 mths-8 yrs). Of the 12 patients who received a LTx alone, 1 needed a KTx 4 years postLTx. Kidney function has remained stable in the others, despite the use of CsA or FK506 (last follow-up creatinine: 1.63 mg/dl (0.93-2.85). Despite long-term immunosuppression, LTx had a dramatic impact on daily quality of life enabling these patients to go back to a fully active life style. Conclusion: This is the largest series of LTx for PLD. LTx (or combined kidney + LTx) offers the chance of a definitive treatment in patients with extensive PLD (diffuse small cysts) that has evolved into severely handicapping hepatomegaly. Patient complaints and chances of definitive palliation offered by LTx must be balanced against the risk of Tx and long-term committment to immunosuppression.