Treatment For End-stage Liver Disease Research Articles

Decellularization of Whole Human Liver Grafts Using Controlled Perfusion for Transplantable Organ Bioscaffolds.

Liver transplantation is the only effective treatment for end-stage liver disease, but absolute donor shortage remains a limiting factor. Recent advances in tissue engineering focus on generation of native extracellular matrix (ECM) by decellularized complete livers in animal models. Although proof of concept has been reported for human livers, this study aims to perform whole liver decellularization in a clinically relevant series using controlled machine perfusion. In this study, we describe a mild nondestructive decellularization protocol, effective in 11 discarded human whole liver grafts to generate constructs that reliably maintain hepatic architecture and ECM components using machine perfusion, while completely removing cellular DNA and RNA. The decellularization process preserved the ultrastructural ECM components confirmed by histology, electron microscopy, and proteomic analysis. Anatomical characteristics of the native microvascular network and biliary drainage of the liver were confirmed by contrast computed tomography scanning. Decellularized vascular matrix remained suitable for normal suturing and no major histocompatibility complex molecules were detected, suggesting absence of allo-reactivity when used for transplantation. After extensive washing, decellularized scaffolds were nontoxic for cells after reseeding human mesenchymal stromal or umbilical vein endothelial endothelium cells. Indeed, evidence of effective recellularization of the vascular lining was obtained. In conclusion, we established an effective method to generate clinically applicable liver scaffolds from human discarded whole liver grafts and show proof of concept that reseeding of normal human cells in the scaffold is feasible. This supports new opportunities for bioengineering of transplantable grafts in the future.

Human bone marrow mesenchymal stem cells suppress the proliferation of hepatic stellate cells by inhibiting the ubiquitination of p27.

Bone marrow mesenchymal stem cells (BMSCs) have considerable therapeutic potential for the treatment of end-stage liver disease. Previous studies have demonstrated that BMSCs secrete growth factors and cytokines that inactivate hepatic stellate cells (HSCs), which inhibited the progression of hepatic fibrosis. The aim of this study was to determine the mechanism by which BMSCs suppress the function of HSCs in fibrosis. Our results showed that co-culture of BMSCs and HSCs induced cell cycle arrest at the G10/G1 phase and cell apoptosis of HSCs, which finally inhibited the cell proliferation of HSCs. Consistent with the cell cycle arrest, co-culture of BMSCs and HSCs increased the abundance of the cell cycle protein p27. Mechanistically, we further uncovered that following the co-culture with BMSCs, the expression level of the E3 ligase S-phase kinase-associated protein 2 (SKP2) that is responsible for the ubiquitination of p27 was decreased, which attenuated the ubiquitination of p27 and increased the stability of p27 in HSCs. Collectively, our results indicated the potential involvement of the SKP2-p27 axis for the inhibitory effect of BSMCs on the cell proliferation of HSCs.

Impact of etiological treatment on prognosis.

Portal hypertension (PHT) is a frequent and severe complication of cirrhosis. PHT may lead to the development of various complications with high mortality. Liver transplantation is the gold standard as a surgical curative treatment for end-stage liver disease. Theoretically, etiological treatment focusing on the pathophysiology of the underlying disease should be the objective of the nonsurgical management of cirrhotic PHT. Chronic viral hepatitis is the major etiology of cirrhosis and PHT. In cirrhotic patients with chronic hepatitis B virus infection, antiviral therapies can suppress viral replication, ameliorate hepatic inflammation, regress fibrosis, and restore liver functional reserve. Moreover, they can delay the progression of liver cirrhosis and ameliorate the severity of PHT. In patients with hepatitis C virus-induced liver cirrhosis, interferon and ribavirin combination therapy provide a favorable long-term prognosis, including lower rates of liver-related and non-liver-related deaths, hepatic decompensation, and hepatocellular carcinoma, particularly in those who have successful eradication of the virus after therapy. In patients with PHT, direct antivirals (DAAs) for hepatitis C virus infection have good safety profiles and excellent viral suppression. Moreover, DAAs can reduce hepatic venous pressure gradient. However, these effects are stronger during the earlier stage of liver cirrhosis. Abstinence is the cornerstone of etiological treatment for alcoholic liver disease. The effects of pharmacological treatments are not satisfactory, and additional studies are mandatory.

Pediatric liver transplantation

With the liver transplantation surgery technology progress and improvement of perioperative management in recent years, pediatric liver transplantation has been gradually developed.The primary disease of liver transplant recipients in children is different from adult liver transplant recipients, mainly with benign end-stage liver disease, such as biliary atresia and some congenital genetic metabolic diseases.Understanding and mastering the indications of child liver transplantation and the timing of surgery can make many children with end-stage liver disease treatment and access to good long-term survival. Key words: Child; Liver transplantation; Prognosis

Functional liver tissue engineering by an adult mouse liver-derived neuro-glia antigen 2-expressing stem/progenitor population

Deaths due to end-stage liver diseases are increasingly registered annually in the world. Liver transplantation is the ultimate treatment for end-stage liver diseases to date, which has been hampered by a critical shortage of organs. The potential of decellularized liver scaffolds (DLS) derived from solid organs as a three-dimensional platform has been evolved as a promising approach in liver tissue engineering for translating functional liver organ replacements, but questions still exist regarding the optimal cell population for seeding in DLS and the preparation of the DLS themselves. The aim of our study was to utilize a sodium dodecyl sulfate decellularization procedure in combination with a low concentration of trypsin (0.005%)-ethylenediaminetetraacetic acid (0.002%) process to manufacture DLS from whole mouse livers and recellularized with hepatic stem/progenitors for use in liver tissue engineering and injured liver treatment. Results showed that the DLS generated with all the necessary microstructure and the extracellular components to support seeded hepatic stem/progenitor cell attachment, functional hepatic cell differentiation. Hepatic differentiation from stem/progenitor cells loaded by DLS was more efficient than that of the stem/progenitor cells in the two-dimensional cell culture model. In summary, the method of DLS loaded by hepatic stem/progenitor cells provided by this study was effective in maintaining DLS extracellular matrix to introduce seeded stem/progenitor cell differentiation, hepatic-like tissue formation and functional hepatic protein production in vitro that promoted functional recovery and survival in a mouse model of dimethylnitrosamine-induced liver cirrhosis after auxiliary heterotopic liver transplantation. Copyright © 2016 John Wiley & Sons, Ltd.

Using zebrafish to model liver diseases-Where do we stand?

The liver is the largest internal organ and performs both exocrine and endocrine function that is necessary for survival. Liver failure is among the leading causes of death and represents a major global health burden. Liver transplantation is the only effective treatment for end-stage liver diseases. Animal models advance our understanding of liver disease etiology and hold promise for the development of alternative therapies. Zebrafish has become an increasingly popular system for modeling liver diseases and complements the rodent models. The zebrafish liver contains main cell types that are found in mammalian liver and exhibits similar pathogenic responses to environmental insults and genetic mutations. Zebrafish have been used to model neonatal cholestasis, cholangiopathies, such as polycystic liver disease, alcoholic liver disease, and non-alcoholic fatty liver disease. It also provides a unique opportunity to study the plasticity of liver parenchymal cells during regeneration. In this review, we summarize the recent work of building zebrafish models of liver diseases. We highlight how these studies have brought new knowledge of disease mechanisms. We also discuss the advantages and challenges of using zebrafish to model liver diseases.

Progress of the application of stem cell therapy for end-stage liver disease

Many risk factors lead to hypohepatia and hepatic failure, causing people suffering from end-stage liver disease. The conventional treatment for end-stage liver disease is not good enough. Orthotopic liver transplantation is effective. However, the high cost, lack of liver source, immune rejection and other factors limit the large-scale clinical application. Thus, cell therapy is a good option. Studies on common cell sources for the treatment of liver disease and the induction of hepatocytes by embryonic stem cells or pluripotent stem cells have made progress. With the development of stem cell technology, cell transplantation has become a new option, which brings hope to people with end-stage liver diseasetransplantation has become a new option. It brings hope to people with end-stage liver disease.

Mesenchymal Stem Cell-Seeded Regenerated Silk Fibroin Complex Matrices for Liver Regeneration in an Animal Model of Acute Liver Failure.

The main limitation of liver transplantation as a treatment for end-stage liver disease or acute liver failure is the scarcity of liver organ donors. To develop an alternative therapy for acute liver failure, mesenchymal stem cell (MSC)-seeded regenerated silk fibroin (RSF) matrices were evaluated in vitro and in vivo. Adipose-derived mesenchymal stem cells (ADSCs) and bone marrow-derived mesenchymal stem cells (BMSCs) were planted and grown on RSF scaffolds to form a scaffold complex. The RSF-MSC scaffold complex (the experimental group) and neat RSF scaffolds (the control group) were then placed onto the liver surface of mice induced by CCl4 and detected after 5, 7, 14, 28, and 60 days. The growth and distribution of MSCs were tracked using fluorescence microscopy and live small animal fluorescence. Liver functions were tested using an automatic biochemistry analyzer. The histological kinetics of RSF complex and liver tissues were observed using hematoxylin & eosin staining. We found that MSCs exhibited good biocompatibility with RSF and differentiated to hepatocyte-like cells in vitro. Liver functions of the mice in the experimental group were significantly improved than that in the control group. Moreover, angiogenesis and hepatocyte-like cells were discovered in the RSF scaffolds in an animal model of acute liver failure on the fifth day and in the second month, respectively. The MSCs-RSF matrices show an obvious therapeutic ability for injured liver function of mice, which is more efficient than the neat RSF scaffolds.

INCIDENCE AND FACTORS ASSOCIATED WITH NEW-ONSET CARDIOMYOPATHIES FOLLOWING LIVER TRANSPLANTATION

Background: Orthotopic liver transplantation (LT) is the only curative treatment for end-stage liver disease, and is a resource-intense, high-risk surgery. While cardiovascular events are the second highest cause of post-LT morbidity, data regarding the development of post-LT cardiomyopathy (CMY)

Research progress in liver regeneration of cirrhosis

Compared with the regeneration ability of normal liver, that of liver with cirrhosis is so weak that its reserve function is insufficient, resulting in a great increase of chance of liver failure after partial hepatectomy, and limiting the development of major hepatectomy. It has been demonstrated that the hepatocytes of cirrhosis still possess the suppressed ability of regeneration. The morphological structures as well as physiological functions of regenerated hepatocytes are not complete. The important mechanisms leading to the impairment of regeneration ability include pathophysiologic changes such as excessive deposition of extracellular matrix and the capillarization, the imba-lance of energy metabolism of hepatocytes and disruptive secretion of sinus endothelial cells and so on. The clinical observation is that many factors can stimulate the regeneration of liver with cirrhosis, including radiofrequency ablation, partial hepatectomy, associated liver partition and portal vein ligation for staged hepatectomy, splenectomy, drugs, cell transplantation, tokines et al. It is of great significance to promote the regeneration ability of liver with cirrhosis associated with various approaches reasonably for enhancing the security of partial hepatectomy and treatment of end-stage liver diseases. Key words: Liver neoplasms; Liver cirrhosis; Liver regeneration; Hepatectomy

The Romanian National Program for Liver Transplantation - 852 Procedures in 815 Patients over 17 Years (2000-2017): A Continuous Evolution to Success.

Background: Liver transplantation (LT) has become an established treatment for end-stage liver disease, with more than 20.000 procedures yearly worldwide. The aim of this study was to analyze the results of Romanian National Program of LT. Methods: Between April 2000 and April 2017, 817 pts received 852 LTs in Romania. Male/female ratio was 487/330, while adult/pediatric ratio was 753/64, with a mean age of 46 years (median 50 yrs; range 7 months - 68 yrs). Main LT indications were HBV cirrhosis (230 pts; 28.2%), HCC (173 pts; 21.2%), and HCV cirrhosis (137 pts; 16.8%). Waiting time and indications for LT, patient and donor demographics, graft features, surgical procedures, and short and long-term outcomes were analyzed. Results: DDLT was performed in 682 pts (83.9%): whole LT in 662 pts (81%), split LT in 16 pts (2.3%), reduced LT in 2 pts (0.2%), and domino LT in 1 pts (0.1%). LDLT was performed in 135 pts (16.5%): right hemiliver in 93 pts (11.4%), left lateral section in 28 pts (3.4%), left hemiliver in 8 pts (1%), left hemiliver with segment 1 in 4 pts (0.5%), and dual graft LDLT in 2 pts (0.2%). Overall major morbidity rate was 31.4% (268 pts), while perioperative mortality was 7.9% (65 pts). Retransplantation rate was 4.3% (35 pts): 27 whole LTs, 3 reduced LTs, 3 split LTs, and 2 LDLT. Long-term overall 1-, 3-, and 5-year estimated survival rates for patients were 87.9%, 81.5%, and 79.1%, respectively. One-, 3-, and 5-year overall mortality on waiting list also decreased significantly over time from 31.4%, 54.1% and 63.5%, to 4.4%, 13.9% and 23.6%, respectively. Conclusions: The Romanian National program for liver transplantation addresses all causes of acute and chronic liver failure or liver tumors in adults and children, using all surgical techniques, with good long-term outcome. The program constantly evolved over time, leading to decreased mortality rate on the waiting list.

Addictive behaviors in liver transplant recipients: The real problem?

Liver transplantation (LT) is the gold standard treatment for end-stage liver disease. Whatever the primary indication of LT, substance abuse after surgery may decrease survival rates and quality of life. Prevalence of severe alcohol relapse is between 11 and 26%, and reduces life expectancy regardless of the primary indication of LT. Many patients on waiting lists for LT are smokers and this is a major risk factor for both malignant tumors and cardiovascular events post-surgery. The aim of this review is to describe psychoactive substance consumption after LT, and to assess the impact on liver transplant recipients. This review describes data about alcohol and illicit drug use by transplant recipients and suggests guidelines for behavior management after surgery. The presence of an addiction specialist in a LT team seems to be very important.

Living Donor Liver Transplantation: A Western Perspective.

Since 1983, liver transplantation has been the established gold standard for the treatment of end-stage liver disease of various etiologies and for an ever-broadening group of patients with hepatocellular carcinoma (HCC).1 Living donor liver transplantation (LDLT) has been and remains a small but increasingly important option for those in need of a liver transplant in the United States. This article reviews the evolution of LDLT in the United States over the past 3 decades, the indications for its use, and the outcomes for both donors and recipients. Also, discussed are the increasing efforts to optimize donor safety while continuing to maintain appropriate recipient outcomes.

Late Gestation Fetal Hepatocytes for Liver Repopulation in the Rat.

Cellular transplantation represents an alternative to liver transplantation for the treatment of end-stage liver disease and liver-based inborn errors of metabolism. In order for cellular transplantation to be successful, an optimal source of cells for transplantation needs to be identified and the molecular mechanisms regulating their engraftment, proliferation, and functional differentiation elucidated. Here we describe a detailed protocol for the isolation, selection, and transplantation into an injured adult rat liver of a defined population of late gestation fetal rat hepatocytes. Also described is the methodology for assessing the purity of the selected cells and the efficiency with which they repopulate the adult liver. Our approach provides an in vivo model to study the molecular pathways involved in liver repopulation.

Concise Review: Liver Regenerative Medicine: From Hepatocyte Transplantation to Bioartificial Livers and Bioengineered Grafts.

Donor organ shortage is the main limitation to liver transplantation as a treatment for end-stage liver disease and acute liver failure. Liver regenerative medicine may in the future offer an alternative form of therapy for these diseases, be it through cell transplantation, bioartificial liver (BAL) devices, or bioengineered whole organ liver transplantation. All three strategies have shown promising results in the past decade. However, before they are incorporated into widespread clinical practice, the ideal cell type for each treatment modality must be found, and an adequate amount of metabolically active, functional cells must be able to be produced. Research is ongoing in hepatocyte expansion techniques, use of xenogeneic cells, and differentiation of stem cell-derived hepatocyte-like cells (HLCs). HLCs are a few steps away from clinical application, but may be very useful in individualized drug development and toxicity testing, as well as disease modeling. Finally, safety concerns including tumorigenicity and xenozoonosis must also be addressed before cell transplantation, BAL devices, and bioengineered livers occupy their clinical niche. This review aims to highlight the most recent advances and provide an updated view of the current state of affairs in the field of liver regenerative medicine. Stem Cells 2017;35:42-50.

Osteoporosis in Pediatric Liver Transplantation.

Liver transplantation provides an important, often life-saving treatment for end-stage liver disease. Osteoporosis post-liver transplantation has been described in adults; however, this has not been described in the pediatric population to date. We present a case of a 13-year-old female patient who underwent an orthotopic liver transplant for cryptogenic liver cirrhosis. Her immunosuppressants were tacrolimus and prednisone. Four months posttransplant, she started complaining of bilateral lower limb pain and limping while walking, progressing to a point where she was almost immobile. Magnetic resonance imagining of the pelvis showed bilateral avascular necrosis involving the weight-bearing surfaces of both femoral heads, in addition to the extensive edema involving both hip joints. Bone mineral densitometry was below normal for her age at the hip and forearm. She was started on high-dose calcium and vitamin D supplement, as well as zoledronic acid with a remarkable symptomatic and functional improvement.

Living Donor Liver Transplantation: Cumulative Insights from Taiwan

This review portrays the living donor liver transplantation (LDLT) scenario in Asia with emphasis on the role played by Taiwan in meeting the objective of offering LDLT as a life-saving procedure in the treatment of end-stage liver disease. In the West, although LDLT has been offered as a solution to overcome the shortage of organs, in the East, liver transplantation is synonymous with LDLT. Endemic hepatitis B and C viral infections remain the most common indication for transplantation in the East. LDLT helps to leverage maximum benefits in patients with hepatocellular carcinoma by a reduction in waiting time mortality and offering scope for adopting more liberal acceptance criteria. Although several challenges unique to this specialty have been faced time and again, there is no denying that LDLT has offered comparable or even better results than that of deceased donor liver transplantation. Minimizing donor risk and ensuring safe donor surgery should be the objective instead of tunnel vision on benefits to the recipient.

Biliary complications following living donor hepatectomy.

Living donor liver transplantation (LDLT) has become increasingly common in an effort to increase organ availability for the treatment of end-stage liver disease. Donor safety is a primary concern in LDLT. The majority of complications experienced by living donors are infectious or biliary in nature. The purpose of this paper was to review the existing literature on biliary complications in living donors. Studies were eligible for inclusion if they were published in English between 2006-present, focused on adult-to-adult LDLT, and were available via PubMed/MEDLINE. A total of 33 studies reporting outcomes from 12,653 donors (right lobe: 8231, left lobe: 4422) were included. Of 33 studies, 12 reported outcomes from right lobe donors, 1 from left lobe donors, 14 compared left and right, and 6 focused specifically on biliary complications. A total of 830 biliary complications (6.6%) were reported, with 75 donors requiring re-operation for biliary complications and 1 donor death attributed to biliary complications. Although bile leaks and strictures are still relatively common following living donor hepatectomy, the majority of complications are minor and resolve with conservative measures. Approximately 6% of living donors will experience a biliary complication and, of these 6%, approximately 9% (total of 0.6% of donors) will require operative management of the biliary complication.

Attenuation of Ischemia-Reperfusion Injury and Improvement of Survival in Recipients of Steatotic Rat Livers Using CD47 Monoclonal Antibody.

Despite the efficacy of orthotopic liver transplantation in the treatment of end-stage liver diseases, its therapeutic utility is severely limited by the availability of donor organs. The ability to rehabilitate marginal organs, such as steatotic allografts, has the potential to address some of the supply limitations of available organs for transplantation. Steatotic livers are more susceptible to ischemia-reperfusion injury (IRI), which is exacerbated by the thrombospondin-1/CD47 pathway through inhibition of nitric oxide signaling. We postulated that CD47 blockade with a monoclonal antibody specific to CD47, clone 400 (CD47mAb400) may reduce the extent of IRI in steatotic liver allografts. Orthotopic liver transplantation was performed using steatotic liver grafts from Zucker rats transplanted into lean recipients. Control IgG or the CD47mAb400 was administered to the donor livers at procurement. Serum transaminases, histological changes, and animal survival were assessed. Hepatocellular damage, oxidative and nitrosative stress, and inflammation were also quantified. Administration of CD47mAb400 to donor livers increased recipient survival and resulted in significant reduction of serum transaminases, bilirubin, triphosphate nick-end labeling staining, caspase-3 activity, oxidative and nitrosative stresses, and proinflammatory cytokine expression of TNF-α, IL-6 and IL-1β. We conclude that administration of CD47mAb400 to donor grafts may reduce IRI through CD47 blockade to result in improved function of steatotic liver allografts and increased survival of recipients and represent a novel strategy to allow the use of livers with higher levels of steatosis.

Liver transplantation in India.

Liver transplantation as an established form of treatment for end-stage liver disease has gained acceptance in India over the last 10 years. Liver transplantation in India has unique features that have contributed to the growth of both deceased donor and living donor transplantations of which living donor currently dominates the picture. Living donor contributes to 80% and deceased donor to 20% of the liver transplants currently performed in India. The majority of these transplants are performed within the private sector with public sector hospitals lagging behind significantly. This article gives an overview of the evolution of liver transplantation in India and the potential future challenges. Liver Transplantation 22 1019-1024 2016 AASLD.