Role Of Orthotopic Liver Transplantation Research Articles

Neutrophil CC1 plays a protective role in orthotopic liver transplantation: views from the perspective of natural compounds

Neutrophil CC1 plays a protective role in orthotopic liver transplantation: views from the perspective of natural compounds

Liver transplantation in the treatment of unresectable hepatic metastasis from neuroendocrine tumors.

Neuroendocrine tumors (NET) are rare neoplasms with generally indolent growth behavior. The liver is the most common site of NET metastasis. The NET metastatic spread to the liver are usually multiple tumors involving bilateral hemilivers. For patients with isolated NET metastasis to the liver, a complete extirpation (R0) resection of both the primary NET and liver metastasis provide the best chance of tumor recurrence-free patient survival. Orthotopic liver transplantation (OLT) presents a viable treatment option for patients with unresectable liver metastasis from NET. Post-OLT outcomes for the patients of NET with liver metastasis (5-year overall survival rate 47-71%) are comparable to those for other indications. However, the high rate of recurrence after OLT (31-57%) remains a clinical obstacle. As such, it is imperative to consider each patient individually and identify prognostic factors that would impact post-OLT outcomes. This article focuses on the role of OLT in the definitive treatment of metastatic liver NET, review patient selection criteria predictive of survival outcomes and post-OLT outcomes for patients.

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury.

Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow-derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress-triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

Antibiotic pretreatment alleviates liver transplant damage in mice and humans.

Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx <10 days; n = 108) and Abx treatment (Abx ≥10days; n = 156) groups; OLT biopsy (Bx) samples were collected 2 hours after OLT (n = 52). Abx in mice mitigated IRI-stressed OLT (IRI-OLT), decreased CCAAT/enhancer-binding protein homologous protein (CHOP) (endoplasmic reticulum [ER] stress), enhanced LC3B (autophagy), and inhibited inflammation, whereas it increased serum prostaglandin E2 (PGE2) and hepatic PGE2 receptor 4 (EP4) expression. PGE2 increased EP4, suppressed CHOP, and induced autophagosome formation in hepatocyte cultures in an EP4-dependent manner. An EP4 antagonist restored CHOP, suppressed LC3B, and recreated IRI-OLT. Remarkably, human recipients of Abx treatment plus OLT (Abx-OLT), despite severe pretransplantation clinical acuity, had higher EP4 and LC3B levels but lower CHOP levels, which coincided with improved hepatocellular function (serum aspartate aminotransferase/serum aspartate aminotransferase [sALT/sAST]) and a decreased incidence of early allograft dysfunction (EAD). Multivariate analysis identified "Abx-free/Abx <10 days" as a predictive factor of EAD. This study documents the benefits of Abx pretreatment in liver transplant recipients, identifies ER stress and autophagy regulation by the PGE2/EP4 axis as a homeostatic underpinning, and points to the microbiome as a therapeutic target in OLT.

Role of liver transplantation in severe alcoholic hepatitis.

Severe alcoholic hepatitis has very high short term mortality and corticosteroids have been the mainstay of treatment for decades. Patients with Lille score >0.45 are considered non-responders to steroids and have poor outcome. Recently Orthotopic Liver Transplantation (OLT) is being increasingly used as rescue treatment for these patients, without waiting for 6 months of abstinence. Liver transplant is the only rescue treatment which can potentially provide long term benefit for patients who are steroid non-responders. However, with scarcity of organs being a concern, all patients of severe alcoholic hepatitis cannot be chosen for transplantation in an arbitrary way. There is a need for development of predictive tools and objective protocols to select patients who can justify the use of precious liver grafts. With a stringent criteria for selection of patients receiving the graft, liver transplantation in severe alcoholic hepatitis can become a viable rescue therapeutic option conferring significant survival advantage of both short- and long-term basis. The optimal criteria for selection will also prevent misuse of the liver donor pool as well as to prevent mortality in salvageable patients. Further research needs to be done to identify subset of patients which are at low risk of recidivism and also cannot be managed with pharmacotherapy alone. We reviewed the current knowledge on role of OLT in patient with acute severe alcoholic hepatitis in the present review.

Heme oxygenase-1 regulates sirtuin-1-autophagy pathway in liver transplantation: From mouse to human.

Liver ischemia-reperfusion injury (IRI) represents a major risk factor of early graft dysfunction and a key obstacle to expanding the donor pool in orthotopic liver transplantation (OLT). Although graft autophagy is essential for resistance against hepatic IRI, its significance in clinical OLT remains unknown. Despite recent data identifying heme oxygenase-1 (HO-1) as a putative autophagy inducer, its role in OLT and interactions with sirtuin-1 (SIRT1), a key autophagy regulator, have not been studied. We aimed to examine HO-1-mediated autophagy induction in human OLT and in a murine OLT model with extended (20hours) cold storage, as well as to analyze the requirement for SIRT1 in autophagy regulation by HO-1. Fifty-one hepatic biopsy specimens from OLT patients were collected under an institutional review board protocol 2 hours after portal reperfusion, followed by Western blot analyses. High HO-1 levels correlated with well-preserved hepatocellular function and enhanced SIRT1/LC3B expression. In mice, HO-1 overexpression by genetically modified HO-1 macrophage therapy was accompanied by decreased OLT damage and increased SIRT1/LC3B expression, whereas adjunctive inhibition of SIRT1 signaling diminished HO-1-mediated hepatoprotection and autophagy induction. Our translational study confirms the clinical relevance of HO-1 cytoprotection and identifies SIRT1-mediated autophagy pathway as a new essential regulator of HO-1 function in IR-stressed OLT.

Role of transplantation in the treatment of benign solid tumors of the liver: a review of the United Network of Organ Sharing data set.

The role of orthotopic liver transplantation for the treatment of benign solid liver tumors (BSLT) is not well defined. To analyze outcomes in the United Network of Organ Sharing data set of patients with a diagnosis of BSLT who underwent transplantation. A retrospective analysis of the United Network of Organ Sharing data set was performed for all (N = 87,280) patients who underwent transplantation for BSLT in the United States from October 1, 1988, through January 31, 2013. Demographics, clinicopathological characteristics, distribution of the procedures by region and state, and overall survival rates. During the study period, 147 liver transplants (0.17%) were to treat BSLT. Sixty-two patients (42.2%) had adenomas, 29 (19.7%) had focal nodular hyperplasia, 25 (17.0%) had hemangiomas, 11 (7.5%) had hepatic epithelioid hemangioendotheliomas, and 20 (13.6%) were classified as having unknown benign tumors. The overall 1-, 3-, and 5-year survival rates were 90.9%, 85.2%, and 81.8%, respectively. Using multivariable analysis, we found that age was the only independent factor associated with patient survival. The overall 5-year survival rate for patients older than 50 years was 88% compared with 91% in younger individuals (95% CI, 148-384; P = .005). Region 3 (Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, and Puerto Rico) contributed the maximum number (33 [22.4%]) of these transplants. Although liver transplantation cannot be considered a first-line treatment, it is a valid therapeutic option in selected patients who are not amenable to resection. Only 0.17% of the transplants in the United States are performed for this indication, with satisfying long-term results. Age was an independent predictor of patient survival. Further studies are needed to better understand the role of liver transplantation in the treatment of BSLT.

To evaluate the role of OLT on splenomegaly of portal hypertension by the radiological changes of splenic morphology and collaterals

To explore the effect of orthotopic liver transplantation (OLT) on portal hypertension by observing the radiological changes of splenic volume and collaterals before and after OLT. In our hospital 56 patients performing OLT due to cirrhosis, portal hypertension and splenomegaly were classified into five groups according to their following-up time: A (≤3 months), B (>3-6 months), C (>6-12 months), D (>12-24 months), and E (>24 months). Twenty health people were chose as control group (F). The splenic width, thickness, length, volume, diameter of portal and splenic vein and collaterals were measured and observed in every patient of six groups before and after OLT respectively. After OLT, the splenic volume decreased by 25.4%, 27.8%, 21.9%, 25.2%, 27.7% in five groups respectively, which was still larger than the normal group (P<0.05). Gastroesophageal varices in 31 cases (81.6%, 31/36) became normal after OLT. The opened umbilical vein disappeared and the retroperitoneal varices persisted in five cases after OLT. Splenomegaly and opened collaterals can be relieved by OLT effectively. The splenic volume didn't change obviously until it decreased by 25% in the three months after OLT. Gastroesophageal varices can be removed in most of patients after OLT. The splenomegaly could last paralled with the splenic vein and retroperitoneal varices after OLT. After OLT, correct disposal of splenic and collateral changes could improve the success rate and the long-term treatment effect of OLT.

Cardiotrophin-1, an antiinflammatory cytokine; is there a therapeutic role in orthotopic liver transplantation?

Cardiotrophin-1, an antiinflammatory cytokine; is there a therapeutic role in orthotopic liver transplantation?

Orthotopic liver transplantation in combination with neoadjuvant therapy

Surgical resection is the primary modality of treatment for hilar and intrahepatic cholangiocarcinoma (HCCA-ICCA). For unresectable early-stage HCCA, excellent long-term tumor recurrence-free patient survival has been achieved using a strict regimen of preoperative staging and neoadjuvant chemoradiation treatment followed by orthotopic liver transplantation (OLT). However, in the case of unresectable ICCA, data on outcomes after OLT are limited. The present article reviews the current literature on the surgical treatment of ICCA focusing on the role of OLT in combination with neoadjuvant therapy and risk stratification of patients being considered for transplantation for unresectable ICCA. Numerous studies reported poor survival outcomes after OLT for ICCA. Recent data using a combination of neoadjuvant therapy followed by OLT in appropriately selected patients with unresectable ICCA demonstrated promising disease recurrence-free survival. Risk stratification for patient selection is crucial to optimize survival outcomes. Excellent long-term disease recurrence-free survival can be achieved in selected patients with unresectable ICCA using a combination of OLT and neoadjuvant therapy. Current data support the expansion of liver transplant criteria for treatment of unresectable ICCA.

Orthotopic Liver Transplantation in Patients with Mixed Hepatocellular Carcinoma-Cholangiocarcinoma

Introduction: Primary liver cancer arises from hepatocytes or biliary epithelium resulting in hepatocellular carcinoma or cholangiocarcinoma, respectively. Mixed hepatocellular carcinoma-cholangiocarcinomas are rare; therefore, medical literature addressing these tumors is limited. As treatment modalities for mixed hepatocellular carcinoma-cholangiocarcinomas are few, the role of orthotopic liver transplantation remains controversial. Aim: To determine the survival outcomes of patients with incidentally discovered mixed hepatocellular carcinomacholangiocarcinomas after orthotopic liver transplantation. Methods and Materials: We present five patients with mixed hepatocellular carcinoma-cholangiocarcinomas who received orthotopic liver transplantation at our institution between September 1998 and July 2011. Characterization of the combined lesion was based on the Allen and Lisa classification scheme: type A: separate neoplasms of liver cell or bile duct cell; type B: different masses that mingle as they grow; and type C: masses that display both features of liver and bile duct cells. Results: Preoperatively, all patients met Milan criteria based on presumed hepatocellular carcinoma prior to orthotopic liver transplantation. Multifocal disease was present in all patients on pathological diagnosis, which was not appreciated during preoperative screening, and histologic characterization of the lesions revealed both Allen and Lisa types A (60%) and C (40%). All of our patients had underlying cirrhosis. The post-operative course was uneventful in all of the cases. Vascular invasion was observed in one patient who developed bone metastases and subsequently died 600 days post-transplant despite post-transplant chemoradiation therapy. The other four patients have remained disease-free; the mean overall survival is 800 days. Our population is unique in prevalence of cirrhosis and multiple hepatic lesions as compared to other case series. Conclusions: Although orthotopic liver transplantation is not recommended for patients with known mixed hepatocellular carcinoma-cholangiocarcinomas, in the event that a patient is transplanted, this case series shows that orthotopic liver transplantation is an acceptable treatment modality with appropriate survival outcomes.

Management of acute liver failure

Acute liver failure (ALF) is a syndrome of diverse etiology, in which patients without previously recognized liver disease sustain a liver injury that results in rapid loss of hepatic function. Depending on the etiology and severity of the insult, some patients undergo rapid hepatic regeneration and spontaneously recover. However, nearly 60% of patients with ALF in the US require and undergo orthotopic liver transplantation or die. Management decisions made by clinicians who initially assess individuals with ALF can drastically affect these patients' outcomes. Even with optimal early management, however, many patients with ALF develop a cascade of complications often presaged by the systemic inflammatory response syndrome, which involves failure of nearly every organ system. We highlight advances in the intensive care management of patients with ALF that have contributed to a marked improvement in their overall survival over the past 20 years. These advances include therapies that limit the extent of liver injury and maximize the likelihood of spontaneous recovery and approaches to enable prevention, recognition and early treatment of complications that lead to multi-organ-system failure, the most common cause of death. Finally, we summarize the role of orthotopic liver transplantation in salvage of the most severely affected patients.

Hilar Cholangiocarcinoma: Current Management

To review the literature with regard to outcome of surgical management for hilar cholangiocarcinoma (Klatskin tumor). Hilar cholangiocarcinoma is a rare tumor with a poor prognosis. Surgical resection provides the only possibility for cure. Advances in hepatobiliary imaging and surgical strategies to treat this disease have resulted in improved postoperative outcomes. We performed a review of the English literature on hilar cholangiocarcinoma from 1990 to 2007. This review included preoperative evaluation, surgical techniques, issues and controversies in management, prognostic variables, and considerations for future directions. Complete resection remains the most effective and only potentially curative therapy for hilar cholangiocarcinoma. Negative resection margins are associated with improved outcomes, and major hepatic resections have enhanced the likelihood of R0 resection. Portal vein embolization may be indicated in selected patients before extensive hepatic resection. Staging laparoscopy should be considered to detect occult metastatic disease. Orthotopic liver transplantation might be applicable for a highly selected subgroup. Surgical resection including major hepatic resection remains the mainstay of treatment of hilar cholangiocarcinoma. Additional evidence is needed to fully define the role of orthotopic liver transplantation. Improvements in adjuvant therapy are essential for improving long-term outcome.

Living Donor Liver Transplantation for Unresectable Liver Metastases From Solid Pseudo-Papillary Tumor of the Pancreas: A Case Report

Solid pseudo-papillary tumors (SPT) are rare primary tumors of the pancreas that primarily affect young women. They are of borderline malignancy, and, unlike other pancreatic malignancies, the prognosis after resection is quite good. However, metastatic disease does occur; the liver is the most common site of tumor dissemination. Herein we have reported a case of a 20-year-old woman who presented with multiple, bilateral liver metastases at 3 years after distal pancreatectomy for SPT of the body and tail of the pancreas. The patient underwent living donor liver transplantation (LDLT) and is alive and disease-free at 24 months after surgery. In this report, we discuss the treatment of liver metastases from SPT, with an emphasis on the possible role of orthotopic liver transplantation (OLT).

Vasoactive intestinal polypeptide secreting pancreatic tumour with hepatic metastases: long term survival after orthotopic liver transplantation

VIPomas are rare neuroendocrine tumours, with metastases often confined to the liver. Orthotopic liver transplantation may be considered in patients with metastases confined to the liver, however the long term benefits have yet to be shown. To discuss the role of orthotopic liver transplantation for neuroendocrine tumours including VIPomas. We describe the case of a very rare pancreatic VIPoma, the therapeutic modalities employed, including orthotopic liver transplantation, and present the results of a relevant literature search. This case is the longest (25 years) reported in the literature for survival from a VIPoma after initial diagnosis and long term survival after liver transplantation (9 years). Liver transplantation for metastatic VIPomas confined to the liver may be justified in selected patients to provide symptomatic hormonal control and pain from tumour bulk, provided there is no extra hepatic disease and medical treatment has been exhausted.

Fulminant hepatic failure in children: Mortality and the role of orthotopic liver transplantation

Fulminant hepatic failure in children: Mortality and the role of orthotopic liver transplantation

Fulminant hepatic failure in children: Mortality and the role of orthotopic liver transplantation

To evaluate the role of orthotopic liver transplantation (OLTx) in fulminant hepatic failure (FHF), defined by coagulopathy (INR>2) with or without encephalopathy in a patient with no identified chronic liver disease.

Liver Transplantation for Combined Hepatocellular Cholangiocarcinoma

Combined hepatocellular cholangiocarcinoma (cHCC-CC) is an uncommon histological variant of primary liver cancer. This combined type of tumour lesion follows an aggressive clinical course with an unfavourable prognosis. Although the role of orthotopic liver transplantation in the management for hepatocellular carcinoma is well defined, to date, there has been no report on its treatment value for cHCC-CC. We report our experience of orthotopic liver transplantation in three patients with cHCC-CC. One patient succumbed to distant metastases 16.5 months after liver transplantation whereas the other two patients continued to survive 35 and 25 months after transplantation, respectively.

Management of end stage liver disease (ESLD): What is the current role of orthotopic liver transplantation (OLT)?

Liver disease due to chronic hepatitis B and C is now a leading cause of morbidity and mortality among HIV-infected patients in the developed world, where classical opportunistic complications of severe immunodeficiency have declined dramatically. Orthotopic liver transplantation (OLT) is the only therapeutic option for patients with end-stage liver disease (ESLD). Accumulated experience in North America and Europe in the last 5 years indicates that 3-year survival in selected HIV-infected recipients of liver transplants was similar to that of HIV-negative recipients. So, HIV infection by itself is not therefore a contraindication for liver transplantation. As survival of HIV-infected patients with ESLD is shorter than non-HIV-infected population, the evaluation for OLT should be made after the first liver decompensation. The current selection criteria for HIV-positive transplant candidates include: no history of opportunistic infections or HIV-related neoplasms, CD4 cell count > 100 cells/mm(3), and plasma HIV viral load suppressible with antiretroviral treatment. For drug abusers, a 2-year abstinence from heroin and cocaine is required, although patients can be in a methadone programme. The main problems in the post-transplant period are pharmacokinetic and pharmacodynamic interactions between antiretrovirals and immunosuppressive drugs, and the management of relapse of HCV infection. Up to now, experience with pegylated interferon and ribavirin is scarce in this population. Currently, HCV re-infection is the main cause for concern.

Liver transplantation for hepatocellular carcinoma: a report of 60 cases

To evaluate the role of orthotopic liver transplantation (OLT) in treatment of hepatocellular carcinoma (HCC) and the selection of recipients. OLT was performed in 60 patients with HCC at Organ Transplantation Centre of the First Affiliated Hospital of Sun Yat-sen University between September 1993 and September 2002. Medical records were retrospectively analyzed with regard to the response to OLT and survival. One-month, 1, 2, 3-year survival rate of 23 liver transplant performed from September 1993 to July 2002 were 73.9%, 60.9%, 43.5% and 29.0%, respectively. One-month, 1, 2-year survival rate of 37 liver transplant performed from August 2000 to September 2002 were 89.2%, 75.8% and 61.2%, respectively. One-month survival rate was significantly greater in the patients with a preoperative liver function of Child A or B than Child C (P < 0.05). One-month, 1, 2, 3-year survival rate of small HCC (single tumor <or= 5 cm diameter or less than 3 tumors and tumors <or= 3 cm maximum diameter, n = 19) and large HCC (tumors > 5 cm diameter, n = 41) were 84.2%, 76.6%, 65.6%, 65.6% and 82.9%, 63.1%, 46.7%, 37.4%, respectively. The median survival of large HCC was 18.0 months and mean survival of small HCC was 29.6 months, respectively. The recurrence rate of small HCC and large HCC were 15.8% and 27.7%, respectively. There was no significant difference between the cumulative survival of small HCC and large HCC. The quality of life of patients with long-term survival was good. HCC associated with cirrhosis can be effectively treated by OLT on condition that no extrahepatic spread and no vascular involvement. OLT is recommended for treatment of small HCC combined with liver cirrhosis, meanwhile, OLT performed in the partial large HCC still is reasonable at the present time.