Fetal liver cell transplantation as a potential alternative to whole liver transplantation?

Because organ shortage is the fundamental limitation of whole liver transplantation, novel therapeutic options, especially the possibility of restoring liver function through cell transplantation, are urgently needed to treat end-stage liver diseases. Groundbreaking in vivo studies have shown that transplanted hepatocytes are capable of repopulating the rodent liver. The two best studied models are the urokinase plasminogen activator (uPA) transgenic mouse and the fumarylacetoacetate hydrolase (FAH)-deficient mouse, in which genetic modifications of the recipient liver provide a tissue environment in which there is extensive liver injury and selection pressure favoring the proliferation and survival of transplanted hepatocytes. Because transplanted hepatocytes do not significantly repopulate the (near-)normal liver, attention has been focused on finding alternative cell types, such as stem or progenitor cells, that have a higher proliferative potential than hepatocytes. Several sources of stem cells or stem-like cells have been identified and their potential to repopulate the recipient liver has been evaluated in certain liver injury models. However, rat fetal liver stem/progenitor cells (FLSPCs) are the only cells identified to date that can effectively repopulate the (near-)normal liver, are morphologically and functionally fully integrated into the recipient liver, and remain viable long-term. Even though primary human fetal liver cells are not likely to be routinely used for clinical liver cell repopulation in the future, using or engineering candidate cells exhibiting the characteristics of FLSPCs suggests a new direction in developing cell transplantation strategies for therapeutic liver replacement. This review will give a brief overview concerning the existing animal models and cell sources that have been used to restore normal liver structure and function, and will focus specifically on the potential of FLSPCs to repopulate the liver.     

Is waiting time a measure of access to liver transplantation? Is shorter necessarily better?

BACKGROUND: The Model for End-Stage Liver Disease (MELD) score has been used since February 2002 to allocate livers for transplantation from deceased donors according to medical need. Allocation based on MELD scores should ensure that sicker patients receive transplants first regardless of transplantation center volume. OBJECTIVE: To determine whether the MELD score at transplantation and waiting time of liver transplant recipients differs by transplantation center volume. DESIGN: Analysis of the Organ Procurement and Transplantation Network database. Centers were classified according to the volume of transplantations performed in 2005: high (> or =100 transplantations), medium (50 to 99 transplantations), and low (<50 transplantations). SETTING: Transplantation centers in the United States. PATIENTS: 20,075 transplant recipients between 27 February 2002 and 30 April 2006. MEASUREMENTS: MELD scores and waiting times of liver transplant recipients. RESULTS: Transplant recipients at high-volume centers had lower MELD scores (35.1% with MELD scores < or =18 vs. 22.7% and 27.0% at medium- and low-volume centers, respectively; P < 0.001), and the median MELD score was 22 compared with 24 at both medium- and low-volume centers. Despite having lower MELD scores, recipients at high-volume centers also experienced shorter waiting times (median waiting time, 69 days vs. 98 days and 94 days at medium-and low-volume centers, respectively; P < 0.001). LIMITATIONS: The definition of transplantation center volume was subjective. The recent implementation of MELD precluded analysis of differences in long-term outcomes related to waiting time or center volume. CONCLUSIONS: The MELD scores and waiting time of liver transplant recipients differed by transplantation center volume. High-volume centers have shorter waiting times and perform more transplantations for less sick patients. The reasons for these differences are unclear but warrant further investigation.     

Vasoconstrictor use in liver transplantation: is there evidence for rational use?

Liver transplantation is a challenging surgical operation performed in recipients with major hemodynamic perturbations related to portal hypertension. The pathophysiologic alterations in portal hypertension include a hyperdynamic circulation and decline in systemic vascular resistance and mean arterial pressure. Cardiac function can also be depressed due to cirrhosis related cardiomyopathy. These cirrhosis related changes often lead to a tenuous state in which organ perfusion is threatened and declines rapidly in the setting of many other insults including blood loss, infection, and use of medications which can cause a decline in blood pressure. This can result in renal failure as well as reduced perfusion of other organs. Additionally, direct consequences of portal hypertension include risk of bleeding from porto-systemic collaterals both in the gastrointestinal tract as well as during abdominal dissection in liver transplantation. In this milieu the management of hemodynamic alterations during liver transplant surgery is a daunting task. Recent approaches have utilized various vasoconstrictor therapies along with judicious use of intravenous fluids to maintain systemic pressures and organ perfusion. Added advantages of this approach include the potential for reducing portal pressure and thus the severity of intra-abdominal hemorrhage during surgery as well as potentially increasing renal blood flow and reducing mesenteric hyperemia. Avoidance of liberal fluid use to maintain systemic pressures also has the advantage of reducing the severity of pulmonary edema and risk of reintubation or prolonged intubation after surgery. Although these approaches utilizing vasoconstrictors are promising, many questions remain. Randomized controlled trials like those performed in the pretransplant population are sparse in the setting of liver transplantation. The optimal vasoconstrictors including combinations and doses have not been defined. Most of the benefits demonstrated thus far have been surrogate outcomes such as reduced transfusion requirement, decreased need for reintubation and improved systemic hemodynamics and reduced portal pressures during surgery. There may be different outcomes of these approaches in patients with varying severities of liver disease. The safety of minimization of fluids, along with vasoconstrictor therapy during liver transplantation has been questioned in patients with higher risk of renal failure including recipients with high MELD scores. Other factors besides disease severity, including organ quality and cold ischemia times, need to be accounted for in future trials. Optimal outcomes including postoperative patient and graft survival, hospital stay and renal function should also be incorporated in future trials of vasoconstrictor therapy during liver transplantation.     

Dualistic role of platelets in living donor liver transplantation: Are they harmful?

Platelets are anucleate fragments mainly involved in hemostasis and thrombosis, and there is emerging evidence that platelets have other nonhemostatic potentials in inflammation, angiogenesis, regeneration and ischemia/reperfusion injury (I/R injury), which are involved in the physiological and pathological processes during living donor liver transplantation (LDLT). LDLT is sometimes associated with impaired regeneration and severe I/R injury, leading to postoperative complications and decreased patient survival. Recent studies have suggested that perioperative thrombocytopenia is associated with poor graft regeneration and postoperative morbidity in the short and long term after LDLT. Although it is not fully understood whether thrombocytopenia is the cause or result, increasing platelet counts are frequently suggested to improve posttransplant outcomes in clinical studies. Based on rodent experiments, previous studies have identified that platelets stimulate liver regeneration after partial hepatectomy. However, the role of platelets in LDLT is controversial, as platelets are supposed to aggravate I/R injury in the liver. Recently, a rat model of partial liver transplantation (LT) was used to demonstrate that thrombopoietin-induced thrombocytosis prior to surgery accelerated graft regeneration and improved the survival rate after transplantation. It was clarified that platelet-derived liver regeneration outweighed the associated risk of I/R injury after partial LT. Clinical strategies to increase perioperative platelet counts, such as thrombopoietin, thrombopoietin receptor agonist and platelet transfusion, may improve graft regeneration and survival after LDLT.     

Are there ethnicity-based differences in the evaluation of individuals with abnormal liver biochemistries?

BACKGROUND/AIMS: Recent studies suggested NAFLD is less infrequent in African Americans (AA) than in Caucasians but it is unclear if this difference is biological or due to under-recognition/under-referral. This study examined if there is an ethnicity-based difference in obtaining liver biochemistries or evaluating abnormal liver biochemistries by primary care physicians. METHODS: This study consisted of 45,016 AA and 49,660 Caucasians seen at our primary care clinics over a 3-year period. From these two groups, we identified patients with elevated aminotransferases (AA: 3676, Caucasians: 4644) and elevated bilirubin (AA: 1295, Caucasians: 1199) based on predefined criteria. Subsequently, we assessed the proportion of patients in each group who had liver-specific evaluation (viral serologies, abdominal imaging or GI clinic visit). RESULTS: Among patients with elevated aminotransferases, compared to Caucasians, AA did not have lower testing for viral hepatitis (26% vs. 25%), imaging (16% vs. 13%) or GI clinic visits (17% vs. 17%). Similarly, we did not observe clinically significant difference in the evaluation of elevated bilirubin between AA and Caucasians (viral serologies: 22% vs. 22%; imaging: 25% vs. 27%; GI clinic: 15% vs. 21%). CONCLUSIONS: Under-recognition and under-referral are not likely to explain the reported ethnic differences in the prevalence of NAFLD.     

How important is donor age in liver transplantation?

The age of liver donors has been increasing in the past several years because of a donor shortage. In the United States, 33% of donors are age 50 years or older, as are more than 50% in some European countries. The impact of donor age on liver transplantation(LT) has been analyzed in several studies with contradictory conclusions. Nevertheless, recent analyses of the largest databases demonstrate that having an older donor is a risk factor for graft failure. Donor age is included as a risk factor in the more relevant graft survival scores, such as the Donor Risk Index, donor age and Model for End-stage Liver Disease, Survival Outcomes Following Liver Transplantation, and the Balance of Risk. The use of old donors is related to an increased rate of biliary complications and hepatitis C virus-related graft failure. Although liver function does not seem to be significantly affected by age, the incidence of several liver diseases increases with age, and the capacity of the liver to manage or overcome liver diseases or external injuries decreases. In this paper, the importance of age in LT outcomes, the role of donor age as a risk factor, and the influence of aging on liver regeneration are reviewed.     

COVID-19 and the liver: Are footprints still there?

The coronavirus disease 2019(COVID-19) hit the entire world as a global pandemic and soon became the most important concern for all patients with chronic diseases. An early trend in higher mortality in patients with acute respiratory distress attracted all researchers to closely monitor patients for the involvement of other systems. It soon became apparent that patients with chronic liver diseases are at increased risk of mortality given their cirrhosis-associated immune dysfunction. Additionall...