Treatment For End-stage Liver Disease Research Articles

A meta-analysis on the incidence of donor-related depression after liver transplant.

Living donor liver transplantation (LDLT) is increasing, yet gaps exist in the understanding of psychological wellbeing of donors after liver transplant. This meta-analysis seeks to evaluate the incidence and risk factors for donor-related depression after liver transplantation. A search was conducted on Medline and Embase database. Articles assessing incidence of depression in LDLT donors were included. Incidence was pooled after Freeman-Turkey double-arcsine transformation. For risk factors, dichotomous variables were analyzed with generalized linear model, while a conventional meta regression with logit transformation was conducted for continuous variables. Of 1069 abstracts, 40 articles underwent full-text review. Seventeen articles were included. The pooled incidence of depression among 1888 LT donors was 7.66% (CI: 4.47-12.80%). Depression rates were significantly higher in Asian compared to Western studies (RR: 1.73, CI: 1.19-2.52, P = 0.0039). Female gender (P < 0.001), Caucasian ethnicity (P = 0.047), employment status (P < 0.001) and lower education levels (P = 0.044) were significantly associated with depression. Donor relationship with recipients was not a significant risk factor. LDLT remains a core aspect of the treatment of end-stage liver disease. However, the high depression rates after LT suggest that there remains room for improvement in the care of donors' mental health post-transplant.

Moving Forward to New Trends in Liver Transplantation

Liver transplantation (LT) is the only recognized effective treatment for end-stage liver disease (ESLD) and acute fulminant liver failure [...]

Using Infodemiology Metrics to Assess Public Interest in Liver Transplantation: Google Trends Analysis.

BackgroundLiver transplantation (LT) is the only curative treatment for end-stage liver disease. Less than 10% of global transplantation needs are met worldwide, and the need for LT is still increasing. The death rates on the waiting list remain too high.ObjectiveIt is, therefore, critical to raise awareness among the public and health care providers and in turn increasingly acquire donors.MethodsWe performed a Google Trends search using the search terms liver transplantation and liver transplant on October 15, 2020. On the basis of the resulting monthly data, the annual average Google Trends indices were calculated for the years 2004 to 2018. We not only investigated the trend worldwide but also used data from the United Network for Organ Sharing (UNOS), Spain, and Eurotransplant. Using pairwise Spearman correlations, Google Trends indices were examined over time and compared with the total number of liver transplants retrieved from the respective official websites of UNOS, the Organización Nacional de Trasplantes, and Eurotransplant.ResultsFrom 2004 to 2018, there was a significant decrease in the worldwide Google Trends index from 78.2 in 2004 to 20.5 in 2018 (–71.2%). This trend was more evident in UNOS than in the Eurotransplant group. In the same period, the number of transplanted livers increased worldwide. The waiting list mortality rate was 31% for Eurotransplant and 29% for UNOS. However, in Spain, where there are excellent awareness programs, the Google Trends index remained stable over the years with comparable, increasing LT numbers but a significantly lower waiting list mortality (15%).ConclusionsPublic awareness in LT has decreased significantly over the past two decades. Therefore, novel awareness programs should be initialized.

Mitochondrial Targeting Therapy Role in Liver Transplant Preservation Lines: Mechanism and Therapeutic Strategies.

The normal function of mitochondria in the hepatic parenchyma can be disrupted by ischemia/reperfusion (I/R) damage during liver transplantation. The pathology of these insults involves various cellular and molecular steps of events that have been extensively researched over decades but are yet to provide complete answers. This review discusses the brief mechanism of the pathophysiology following ischemia/reperfusion injury (IRI) and various targeting strategies that could result in improved graft function.The traditional treatment for end-stage liver disease i.e., liver transplantation, has been complicated by I/R damage. The poor graft function or primary non-function found after liver transplantation may be due to mitochondrial dysfunction following IRI. As a result, determining the sequence of incidents that cause human hepatic mitochondrial dysfunction is crucial; it might contribute to further improvements in the outcome of liver transplantation. Early discovery of novel prognostic factors involved in IRI could serve as a primary endpoint for predicting the outcome of liver grafts as well as promoting the early implementation of novel IRI-prevention strategies. In this review, recent developments in the study of mitochondrial dysfunction and I/R damage are discussed, specifically those concerning liver transplantation. Furthermore, we also explore different pharmacological therapeutic methods that may be used and their connections to mitochondrion-related processes and goals.Although significant progress has been made in our understanding of IRI and mitochondrial dysfunction, further research is needed to elucidate the cellular and molecular pathways underlying these processes to help identify biomarkers that can aid donor organ evaluation.

Advances in the study of mesenchymal stem cells for end-stage liver disease

End-stage liver disease refers to the advanced stage of liver disease caused by various chronic liver damage. Orthotopic liver transplantation is the most important final treatment option, but liver transplantation is still limited by many factors at present. Stem cell transplantation therapy has attracted widespread attention as a potential treatment for end-stage liver disease. This article reviews the research progress of mesenchymal stem cell therapy in end-stage liver disease.

Accuracy of the Chula's formula for calculation of standard liver volume in Thai population

Background: Standard liver volume (SLV) is an important concept in living donor liver transplantation for treatment of end-stage liver disease. Accurate estimation of the SLV of living donor and recipient is crucial to ensure optimal graft function and avoid complications. Objective: 1) to assess the proposed formula for calculation of SLV in Thai population, using computed tomography (CT) volumetric measurement as a gold standard. 2) to evaluate the factors (e.g. age, sex, body weight and body surface area) related to differences between SLV calculated from the proposed formula and CT volumetric measurement. Materials and methods: We evaluated 497 patients underwent contrast-enhanced abdominal multi-detector CT for conditions unrelated to hepatobiliary system with normal liver radiology between October 1, 2014 and August 31, 2015 were included. Calculated SLV by the proposed formula (SLV = 20.76 x body weight) were compared to the total liver volume (TLV) measured from multi-detector CT by using computerized tool automatically. Factors related to the difference between SLV and TLV were evaluated. Result: The aforementioned formula showed a high accuracy in estimating the liver volume with some limitations in overweight or underwent patients. The mean difference between SLV and TLV is 3.36 cm3 with SD of 224.65 cm3. Conclusion: We proposed a new formula ("Chula's standard liver volume") that demonstrates a high accuracy for calculation of SLV in Thai population. Keywords: Liver volume; MDCT; standard liver volume; Thai population

Modified Charlson comorbidity index as a pre-operative selection tool for liver transplantation in elderly patients

Liver transplantation is an effective treatment for end-stage liver disease and hepatocellular carcinoma. The number of elderly patients who undergo liver transplantation is increasing. Although it has been known that the overall outcome in elderly patients is no different from the younger ones, there is no tool to predict the prognosis of elderly patients. Therefore, we hypothesized that modified Charlson comorbidity index (CCI), which includes 5 comorbidities, can predict the outcome of elderly patients. We conducted a retrospective study of 155 patients over 65 years old who underwent liver transplantation at Seoul National University Hospital from August 2011 to May 2019. Modified CCI score (MODIFIED CCI) including coronary disease, Chronic Obstructive Pulmonary Disease, Diabetes Mellitus, connective tissue disease, and renal insufficiency was calculated. Then, recipients were subcategorized into 2 groups; low MODIFIED CCI group (0-1), and high MODIFIED CCI group (2-5). Proportional hazards analysis was performed to determine the independent effect of each variable on post-transplantation survival using MODIFIED CCI, age at transplantation, gender, Child-Turcotte-Pugh score, Model for End-Stage Liver Disease (MELD) score, and 5-Factor Modified Frailty Index. There were 41 patients in the high MODIFIED CCI group. The high MODIFIED CCI group showed significantly lower 1-, 3- month, and 1, 3, 5-year survival than the low MODIFIED CCI group. In the Cox regression, the MODIFIED CCI (HR = 2.409), gender (HR = 0.447), and MELD score (HR = 1.107) remained. Survival after LT is diminished in patients with preoperative high MELD and MODIFIED CCI score >1. The MODIFIED CCI can be used.

Long‐Term Persistence of Fetal Hepatocyte Gene Signature Following Transplantation to Adult Liver

Background Hepatic cell transplantation (HCT) offers a potential treatment for end-stage liver disease which mitigates the issues of organ supply for whole-liver orthotopic transplantation, but HCT is limited by the short duration of efficacy of transplanted adult cells. Fetal hepatocytes have shown durable long-term posttransplant potency in clinical trials, but ethical concerns hinder their routine procurement. By comparing the transcriptome of posttransplant fetal colonies to pretransplant fetal cells, and contrasting them with adult hepatocytes, we hope to characterize the gene expression differences between fetal and adult hepatocytes that are retained in fetal cells following HCT. We aim to identify mechanisms among these responsible for the durable fetal proliferative phenotype, and potentially elucidate new strategies to improve HCT for clinical use. Methods: Using the Dipeptidyl Peptidase IV rat model, we performed Laser Capture Microdissection (LCM) on sections of liver 10 months after fetal HCT. We collected paired fetal- and adult-origin hepatocytes from multiple biological replicates. Isolated total RNA from these samples were submitted for RNA-Seq by GENEWIZ. To investigate pretransplant cells, adult and fetal hepatocytes were prepared from digested whole liver. Fetal hepatocytes were immunopurified by using the hepatic marker LAP, as well the putative bipotential marker OC.2. Isolated RNA was run on Affymetrix microarrays. The results from these studies were analyzed together in R. Results: Our posttransplant RNA-Seq results when analyzed by 3D PCA showed a distinct clustering effect by tissue type. We observed over 700 significantly (FDR<0.05) differentially expressed genes between the fetal colonies and surrounding adult host hepatocytes. Gene Ontology (GO) analysis of these sets shows that the genes expressed in fetal colonies play a role in membrane transport processes, while those expressed in adult host correspond to lipid metabolism activity. We demonstrate here that the fetal hepatocyte transcriptome is partially maintained 10 months posttransplant. This likely reflects the durably-retained differences in regulatory histone post-translational modifications (hPTMs) we have previously identified in this same population. Future studies will explore the regulatory mechanisms linked to critical growth-regulating genes.

Moderately Macrosteatotic Livers Have Acceptable Long-Term Outcomes but Higher Risk of Immediate Mortality

Liver transplantation is the most effective treatment for end-stage liver disease (ESLD). Whether moderately macrosteatotic livers (30%-60%) represent a risk for worsened graft function is controversial. The uncertainty, in large part, is owing to the heterogeneous steatosis grading. Our aim was to determine the short- and long-term outcomes of moderately macrosteatotic allografts that were graded according to a standardized institutional protocol. We performed a retrospective analysis of transplants performed between 1994 and 2014. All patients with allografts biopsied pretransplantation were included. Relevant donor and recipient variable were recorded. Moderately macrosteatotic livers were compared with mildly macrosteatotic and nonsteatotic livers. Primary outcomes of interest were patient survival at 90 days, 1 year, and 5 years. Cox regression analyses were carried out to compare survival between the 2 groups. We compared 65 allografts with moderate macrosteatosis and 810 with no or mild macrosteatosis. Patients with moderately macrosteatotic allografts were 2.69 times as likely to die within the first 90 days after transplant (75.1% vs 91.6% survival) after adjusting for donor age, donor race, recipient age, recipient race, recipient body mass index, recipient diabetes, presence of hepatocellular carcinoma, days on waitlist, Model for End-Stage Liver Disease (MELD) score at transplantation, cold ischemia time. However, for recipients who survive 90 days, moderately macrosteatotic allografts had comparable long-term survival. Our study shows that moderate macrosteatosis is a strong predictor of early but not late mortality. Further studies are needed to distinguish the specific cohort of patients for whom moderately macrosteatotic allografts will lead to acceptable outcomes.

Mesenchymal stem cell therapy for liver disease: current status and future perspectives.

Liver transplantation is the gold standard for the treatment of end-stage liver disease. However, a shortage of donor organs, high cost, and surgical complications limit the use of this treatment. Cellular therapies using hepatocytes, hematopoietic stem cells, bone marrow mononuclear cells, and mesenchymal stem cells (MSCs) are being investigated as alternative treatments to liver transplantation. The purpose of this review is to describe studies using MSC transplantation for liver diseases based on the reported literature and to discuss prospective research designed to improve the efficacy of MSC therapy. MSCs have several properties that show potential to regenerate injured tissues or organs, such as homing, transdifferentiation, immunosuppression, and cellular protective capacity. Additionally, MSCs can be noninvasively isolated from various tissues and expanded ex vivo in sufficient numbers for clinical evaluation. Currently, there is no approved MSC therapy for the treatment of liver disease. However, MSC therapy is considered a promising alternative treatment for end-stage liver diseases and is reported to improve liver function safely with no side effects. Further robust preclinical and clinical studies will be needed to improve the therapeutic efficacy of MSC transplantation.

Navigating immune cell immunometabolism after liver transplantation.

Liver transplantation (LT) is the most effective treatment for end-stage liver diseases. The immunometabolism microenvironment undergoes massive changes at the interface of immune functionalities and metabolic regulations after LT. These changes considerably modify post-transplant complications, and immune cells play an influential role in the hepatic immunometabolism microenvironment after LT. Therefore, adequate studies on the complex pathobiology of immune cells are critical to prevent post-transplant complications, and the interplay between cellular metabolism and immune function is evident. Furthermore, immune cells perform their specified functions, such as activation or differentiation, accompanied by alterations in metabolic pathways, such as metabolic reprogramming. This transformation remarkably affects post-transplant complications like rejection. By targeting different metabolic pathways, regulations of metabolism are employed to shape immune responses. These differences of metabolic pathways allow for selective regulation of immune responses to further develop effective therapies that prevent graft loss after LT. This review examines immune cells in the hepatic immunometabolism microenvironment after LT, summarizes possible mechanisms and potential prevention on rejection to acquire immune tolerance, and offers some insight into references for scientific research along with clinical treatment.

Progress in basic and clinical and clinical research of a cell therapy for end-stage liver disease

Clinically, the incidence of end-stage liver disease including decompensated cirrhosis and liver failure is high, which seriously threatens people's health. The existing comprehensive internal medicine treatment is ineffective, and liver transplantation is still the most effective treatment method. However, the shortage of matching liver donors and other reasons constrain the development of liver transplantation, thus limiting the treatment of patients with end-stage liver disease. In recent years, domestic and foreign scholars have conducted many pre-clinical and clinical trials using a variety of cells, and have achieved certain results, providing a new method for the treatment of end-stage liver disease. This article reviews and discusses the existing problems, research status and application progress of varieties of cell therapy for end-stage liver diseases.

Comparative study of the safety and efficacy of SMOFlipid vs non SMOFlipid as TPN for liver transplantation

BackgroundLiver transplantation (LT) is one of the widely recognised and leading treatments for end-stage liver disease. Nutrition impacts its success. Total parenteral nutrition (TPN) is usually prescribed for patients recommended prolonged fasting after LT. The supplement of SMOFlipid (soybean oil, MCT oil, olive oil, and fish oil) is easily metabolised to produce energy, and it possesses anti-inflammatory effects; however, SMOFlipid emulsion use raises concerns regarding coagulopathy after LT. This study investigated the postoperative correlation between SMOFlipid and coagulation in LT. Materials and methodsThe medical records of 54 recipients of living donor LT between January 2012 and June 2015 were retrospectively reviewed. Patients with pretransplant platelet count <40,000/μL and >40,000/μL were assigned to the non-SMOFlipid (n = 23) group and the SMOFlipid (n = 31) group, respectively. ResultsThe coagulation and nutrition profile of patients improved significantly after TPN support. No significant difference was observed in the coagulation profile between SMOFlipid and non-SMOFlipid groups. Although the SMOFlipid group exhibited a higher platelet count than the non-SMOFlipid group on day 7 (P < 0.001), no significant differences were observed in the platelet count on 14 and 30 days after TPN support between the 2 groups. ConclusionTPN using SMOFlipid after LT is a good strategy for improving nutritional status without increasing the risks of bleeding and coagulation in patients intolerant of early enteral nutrition. Moreover, SMOFlipid use may not cause coagulopathy up to 14 days after LT. Overall, SMOFlipid provides nutritional benefits without increasing the risk of bleeding.

Pregnancy Outcomes After Liver Transplantation: A Systematic Review and Meta-Analysis.

Liver transplantation (LT) remains the gold standard for treatment of end-stage liver disease. Given the increasing number of liver transplantation in females of reproductive age, our aim was to conduct a systematic review and meta-analysis evaluating pregnancy outcomes after LT. MEDLINE, Embase, and Scopus databases were searched for relevant studies. Study selection, quality assessment, and data extraction were conducted independently by 2 reviewers. Estimates of pregnancy-related outcomes in LT recipients were generated and pooled across studies using the random-effects model. A comprehensive search identified 1,430 potential studies. Thirty-eight studies with 1,131 pregnancies among 838 LT recipients were included in the analysis. Mean maternal age at pregnancy was 27.8 years, with a mean interval from LT to pregnancy of 59.7 months. The live birth rate was 80.4%, with a mean gestational age of 36.5 weeks. The rate of miscarriages (16.7%) was similar to the general population (10%-20%). The rates of preterm birth, preeclampsia, and cesarean delivery (32.1%, 12.5%, and 42.2%, respectively) among LT recipients were all higher than the rates for the general US population (9.9%, 4%, and 32%, respectively). Most analyses were associated with substantial heterogeneity. Pregnancy outcomes after LT are favorable, but the risk of maternal and fetal complications is increased. Large studies along with consistent reporting to national registries are necessary for appropriate patient counseling and to guide clinical management of LT recipients during pregnancy.

Wnt/-Catenin Signaling and Liver Regeneration: Circuit, Biology, and Opportunities.

The liver is uniquely bestowed with an ability to regenerate following a surgical or toxicant insult. One of the most researched models to demonstrate the regenerative potential of this organ is the partial hepatectomy model, where two thirds of the liver is surgically resected. The remnant liver replenishes the lost mass within 1014 days in mice. The distinctive ability of the liver to regenerate has allowed living donor and split liver transplantation. One signaling pathway shown to be activated during the process of regeneration to contribute toward the mass and functional recovery of the liver is the Wnt/-catenin pathway. Very early after any insult to the liver, the cellmolecule circuitry of the Wnt/-catenin pathway is set into motion with the release of specific Wnt ligands from sinusoidal endothelial cells and macrophages, which, in a paracrine manner, engage Frizzled and LDL-related protein-5/6 coreceptors on hepatocytes to stabilize -catenin inducing its nuclear translocation. Nuclear -catenin interacts with T-cell factor family of transcription factors to induce target genes including cyclin D1 for proliferation, and others for regulating hepatocyte function. Working in collaboration with other signaling pathways, Wnt/-catenin signaling contributes to the restoration process without any compromise of function at any stage. Also, stimulation of this pathway through innovative means induces liver regeneration when this process is exhausted or compromised and thus has applications in the treatment of end-stage liver disease and in the field of liver transplantation. Thus, Wnt/-catenin signaling pathway is highly relevant in the discipline of hepatic regenerative medicine.

Early Experiences of Liver Transplantation in A Newly Opened Hospital

Since the first human liver transplantation (LT) performed in 1963, LT has been most effective treatment for end-stage liver diseases and for selected patients with hepatic neoplasms. Herein we will report early experience of liver Transplantation in a newly opened hospital on April, 2019.

The state of Ghanaian liver medicine.

This paper aims to highlight the challenges in managing liver diseases in Ghana and the efforts needed to improve services to help curb the high rate of liver mortality in the young adults. Ghana is a rising, middle-income West African country with well-established administrative systems for healthcare, albeit with hospitals lacking modern equipment and being devoid of infrastructure for sophisticated interventional procedures. Although liver disease is common, due to the high prevalence of chronic viral hepatitis B and C infection, antiviral drugs are commonly unavailable, even in the rare instances where they can be afforded. Hospital wards and outpatient clinics are usually over-crowded with long waiting times and limited doctor-patient time interaction. Treatment for end-stage liver disease can be a challenge, with limited endoscopic services, which are centered in the big cities and with expertise which is not widespread. The training program in endoscopic therapies by the Mayo Clinic (Rochester, Minnesota, USA), with faculty coming to Ghana to disseminate practical skills during a “training of trainers” program has gone a long way spreading the knowledge of managing life-threatening complications, such as variceal hemorrhage, albeit on a small scale in national terms. Collaboration between institutions from well-resourced and poorly-resourced countries exemplifies how such partnerships can go a long way in helping to support local training needs and the development of transferrable skills. Such partnerships may effectively provide healthcare workers with adequate training, with hepatology treatment protocols that are adapted to the local environment and thus allowing contextualisation of generic guidelines from the developed world and making them applicable to local settings.

Perioperative Management for Liver Transplantation with DSA Positive Patients

Background: Liver transplantation is an accepted treatment for end-stage liver disease. Despite improvements of the surgical techniques, organ preservation methods, and immunosuppressive therapy, antibody mediated rejection is still big problem. It has been reported that the existence of donor-specific antibodies (DSA) is correlated with rejection and with an increased risk of early mortality. We described our treatment and prognosis about the patient who has undergone liver transplantation with DSA. Methods: 16 patients among 87 patients of recipient who has undergone liver transplantation in our department from September 2011 to December 2018. In each patient, the type of DSA and the MFI were measured before liver transplantation. A high DSA titer was defined as a normalized, trimmed MFI value ≥10000. Patients received the standard immunosuppressive protocol for liver transplantation, including steroids, tacrolimus, and mycophenolate mofetil, with addition of rituximab more than two weeks before transplantation and took medication such as tacrolimus and mycophenolate mofetil one week before the transplantation. During operation, each patient underwent splenectomy. Results: 7 patients have high titer DSA, and each patient has a desensitization method that described before. Only one patient was dead because of other disease. 9 patients are still arrived without severe rejection. Conclusion: If the patients who has DSA was undergone right desensitization methods, we can get good survival rate.

Surgical treatment of breast cancer in liver transplant recipients: a cross-sectional analysis

Presenter: David Stillman MD | Albany Medical Center Background: Orthotopic liver transplantation is the gold standard for curative treatment of end-stage liver disease. Since Theodore Starzl performed the first human liver transplant in 1963, outcomes have dramatically improved as understanding of the immune response has grown hand-in-hand with the burgeoning armamentarium of immunosuppressant medications. Increased graft and host survival has drawn the medical community’s attention to the long-term care of this unique patient population, including the relationship between transplantation, immunosuppression, and malignancy. Breast cancer is the most common non-skin cancer in women, and outcomes research investigating the intersection of breast cancer and liver transplant is sparse. Here, we present a cross-sectional study examining outcomes of patients with history of liver transplant who underwent lumpectomy or mastectomy using data queried from the National Inpatient Sample database from 2005 to 2014. Methods: The 99 liver transplant patients who met our criteria were compared to 273,841 breast cancer patients, with both groups having tissue diagnosis of malignancy or carcinoma in situ and having undergone uni- or bilateral mastectomy or lumpectomy, with or without reconstruction. Hospital and patient-level characteristics were compared with student T, Mann-Whitney, and chi squared tests where appropriate, revealing grossly similar populations and facilities. Elixhauser Comorbidity Index scores were calculated to compare degree of comorbidity. Logistic regression models were employed for outcomes investigation. Financial and length of stay data were evaluated with linear regression modeling, adjusted based on Consumer Price Index 2020. Multivariate logistic regressions were used to compare outcomes between hospital settings. Results: Elixhauser Comorbidity Index scores were calculated with a significant difference in scores >10, 20.5% in transplant recipients vs 10.2% in those without (p = 0.001). Logistic regression models showed no statistically significant difference in morbidity between groups with the exception of increased rate of acute renal failure in the transplanted population (9.9% vs 0.6%, p < 0.001). Financial and length of stay data evaluated with linear regression modeling showed significantly higher median total hospital charges in the transplanted cohort ($63,724 vs $43,002; p < 0.001), however multivariate logistic regressions used to compare outcomes between hospital settings showed this difference in cost of care disappeared in transplant and teaching centers. Conclusion: Overall, this study shows that despite the increased complexity of caring for liver transplant recipients with breast cancer, teaching hospitals and transplant centers deliver cost-effective surgical treatment of breast cancer without increased mortality and morbidity compared to the non-transplanted population.

Research progress on hepatic machine perfusion.

Nowadays, liver transplantation is the most effective treatment for end-stage liver disease. However, the increasing imbalance between growing demand for liver transplantation and the shortage of donor pool restricts the development of liver transplantation. How to expand the donor pool is a significant problem to be solved clinically. Many doctors have devoted themselves to marginal grafting, which introduces livers with barely passable quality but a high risk of transplant failure into the donor pool. However, existing common methods of preserving marginal grafts lead to both high risk of postoperative complications and high mortality. The application of machine perfusion allows surgeons to make marginal livers meet the standard criteria for transplant, which shows promising prospect in preserving and repairing donor livers and improving ischemia reperfusion injury. This review summarizes the progress of recent researches on hepatic machine perfusion.