Therapeutic possibilities of stem cells in the treatment of liver diseases

Cell therapy and the use of stem cells in the treatment of liver diseases is still in the research phase. Nevertheless, the diversity of stem cells in terms of their origin, characteristics and potential for differentiation provides a wide spectrum of possibilities for the treatment of liver diseases. The present article describes the main types of stem cells and their potential for the treatment of liver diseases, as well as the main therapeutic strategies that are currently being explored for the treatment of these diseases through cell therapy. In addition, the main preclinical and clinical studies suggesting that stem cells could become an effective therapeutic alternative in distinct liver diseases are discussed.     

Critical role of estrogen in the progression of chronic liver diseases

BackgroundEstrogens regulate sexual function and also have a significant role in various pathophysiological processes. Estrogens have a non-reproductive role as the modulators of the immune system, growth, neuronal function, and metabolism. Estrogen receptors are expressed in the liver and their impaired expression and function are implicated with obesity and liver associated metabolic dysfunctions. The purpose of the current review is to discuss the disparity role of estrogens on several forms of liver diseases.Data sourcesA comprehensive search in PubMed and EMBASE was conducted using the keywords “estrogens and liver diseases”, “estradiol and liver diseases”, “hormones and liver diseases”, “endocrine function in liver diseases”, and “female hormones in liver diseases”. Relevant papers published before September 30, 2019 were included.ResultsThe present review confirms the imperative role of estrogen in various forms of chronic liver diseases. Estrogens play a key role in maintaining homeostasis and make the liver less susceptible to several forms of chronic liver diseases in healthy premenopausal individuals. In contrast, clinical studies also showed increased estrogen levels with chronic liver diseases.ConclusionsSeveral studies reported the protective role of estrogens in chronic liver diseases and this has been widely accepted and confirmed in experimental studies using ovariectomized rat models. However, in a few clinical studies, increased estrogen levels are also implicated in chronic liver diseases. Therefore, further studies are warranted at molecular level to explore the role of estrogen in various forms of chronic liver diseases.     

Gut microbiota and liver diseases

Several studies revealed that gut microbiota are associated with various human diseases,e.g.,metabolic diseases,allergies,gastroenterological diseases,and liver diseases.The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein,and the liver-gut axis is important to understand the pathophysiology of several liver diseases,especially non-alcoholic fatty liver disease and hepatic encephalopathy.Moreover,gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis.Based on theseprevious findings,trials using probiotics have been performed for the prevention or treatment of liver diseases.In this review,we summarize the current understanding of the changes in gut microbiota associated with various liver diseases,and we describe the therapeutic trials of probiotics for those diseases.     

Functional interaction of endoplasmic reticulum stress and hepatitis B virus in the pathogenesis of liver diseases

Hepatitis B virus(HBV) is a non-cytopathic virus that causes acute and chronic inflammatory liver diseases,often leading to the pathogenesis of hepatocellular carcinoma(HCC). Although many studies for the roles of HBV on pathogenesis of the liver diseases,such as non-alcoholic fatty liver disease(NAFLD),hepatic inflammation,cirrhosis,and HCC,have been reported,the mechanisms are not fully understood. Endoplasmic reticulum(ER) and mitochondria have the protective mechanisms to restore their damaged function by intrinsic or extrinsic stresses,but their chronic dysfunctions are associated with the pathogenesis of the various diseases. Furthermore,HBV can affect intraor extracellular homeostasis through induction of ER and mitochondrial dysfunctions,leading to liver injury. Therefore,the mechanism by which HBV induces ER or mitochondrial stresses may be a therapeutic target for treatment of liver diseases.     

外泌体在非肿瘤性肝脏疾病中的研究进展

肝脏是人体重要的代谢和免疫器官,外泌体是一种由细胞分泌的细胞外囊泡,携带蛋白质、脂质、DNA和RNA等多种分子,研究发现其在多种肝脏疾病中发挥重要作用。阐述了外泌体在非肿瘤性肝脏疾病发病机制中的作用,以及将它们作为疾病诊断生物标志物和治疗手段的相关研究进展,认为应该深入研究外泌体的生物发生、释放及其在疾病中的确切机制,为非肿瘤性肝脏疾病的防治提供依据。     

Probiotics in hepatology: An update

The gut–liver axis plays an important role in the pathogenesis of various liver diseases. Probiotics are living bacteria that may be used to correct disorders of this axis. Notable progress has been made in the study of probiotic drugs for the treatment of various liver diseases in the last decade. It has been proven that probiotics are useful for hepatic encephalopathy, but their effects on other symptoms and syndromes of cirrhosis are poorly studied. Their effectiveness in the treatment of metabolic associated fatty liver disease has been shown both in experimental models and in clinical trials, but their effect on the prognosis of this disease has not been described. The beneficial effects of probiotics in alcoholic liver disease have been shown in many experimental studies, but there are very few clinical trials to support these findings. The effects of probiotics on the course of other liver diseases are either poorly studied (such as primary sclerosing cholangitis, chronic hepatitis B and C, and autoimmune hepatitis) or not studied at all (such as primary biliary cholangitis, hepatitis A and E, Wilson's disease, hemochromatosis, storage diseases, and vascular liver diseases). Thus, despite the progress in the study of probiotics in hepatology over the past decade, there are many unexplored and unclear questions surrounding this topic.     

Cautiously using natural medicine to treat liver problems

Natural medicine is a system of therapy that administrates natural agents and their derivatives to treat human diseases.This medicine has been used to treat many kinds of human diseases for thousands of years.The treatment protocols of natural medicine are integrative in nature,and are required to utilize the most appropriate therapies to address the needs of the individual patient.Because of the relative convenience,safety and efficacy,natural medicine is now increasing worldwide.Naturopathic doctors are licensed in many areas of the world and regulated partly by law in these areas,which is quite different from various other forms of complementary and alternative medicine.Liver diseases,such as hepatitis,liver cirrhosis and liver carcinoma,are serious health problems worldwide.Nearly half of the natural agents used in treatment of liver diseases today are natural products and their derivatives.Although natural medicine is beneficial and safe,physicians should pay close attention to the potential side-effects of the naturopathic agents,which lead to liver injury,interstitial pneumonia and acute respiratory failure.Therefore,when administrating naturopathic protocols to patients for the treatment of liver diseases,we should try our best to prevent and avoid as much as possible the negative impact of these medicines.This article highlights the current practice and recommended improvement of natural medicines in the treatment of liver diseases and gives some specific examples to emphasize the prevention and management of adverse reactions of the natural agents and suggests that natural medicine should be cautiously used to treat liver problems.     

重视肝纤维化的诊断和治疗

肝纤维化是多种慢性肝病进展至肝硬化的临床病理过程，其病因复杂，明确病因至关重要，准确判断肝纤维化程度是观察抗纤维化疗效和确定治疗终点的基础。目前我国肝纤维化的病因仍以慢性乙型病毒性肝炎为主，但近年来疾病谱已发生了一定变化，其中酒精性和非酒精性脂肪性肝病、自身免疫性肝病、胆汁淤积性肝病所占比例相对增加。各种无创性诊断模型在评价肝纤维化的分期和分级方面有一定的临床用途，但肝活检仍是肝纤维化分级的金标准。肝纤维化的治疗应立足于病因，并积极探索适用于临床的抗肝纤维化药物。     

酒精性肝病患者肠道微生态变化研究进展

目的 酒精性肝病(ALD)是全球肝脏疾病相关死亡的重要原因之一,已经成为全球范围内的卫生健康负担。越来越多的证据证明饮酒、肠道微生物失调和肝脏疾病之间存在密切的联系,肠道屏障破坏导致细菌及其产物的移位是关键的致病因素。近年来,通过对饮酒、肠道微生态与ALD进展之间相互作用的研究越来越多,寻找新的生物标志物和治疗靶点也成为预防和治疗ALD的热点。     

Herbal medicine in the treatment of liver diseases.

Herbal drugs have become increasingly popular and their use is widespread. Licensing regulations and pharmacovigilance regarding herbal products are still incomplete and clearcut proof of their efficacy in liver diseases is sparse. Nevertheless, a number of herbals show promising activity including silymarin for antifibrotic treatment, phyllantus amarus in chronic hepatitis B, glycyrrhizin to treat chronic viral hepatitis, and a number of herbal combinations from China and Japan that deserve testing in appropriate studies. Apart from therapeutic properties, reports are accumulating about liver injury after the intake of herbals, including those advertised for liver diseases. Acute and/or chronic liver damage occurred after ingestion of some Chinese herbs, herbals that contain pyrrolizidine alkaloids, germander, greater celandine, kava, atractylis gummifera, callilepsis laureola, senna alkaloids, chaparral and many others. Since the evidence supporting the use of botanicals to treat chronic liver diseases is insufficient and only few of them are well standardised and free of potential serious side effects, most of these medications are not recommended outside clinical trials. Particularly with regard to the latter, adequately powered randomised-controlled clinical trials with well-selected end points are needed to assess the role of herbal therapy for liver diseases.     

Liver physiology and liver diseases in the elderly

The liver experiences various changes with aging that could affect clinical characteristics and outcomes in patients with liver diseases.Both liver volume and blood flow decrease significantly with age.These changes and decreased cytochrome P450 activity can affect drug metabolism,increasing susceptibility to drug-induced liver injury.Immune responses against pathogens or neoplastic cells are lower in the elderly,although these individuals may be predisposed to autoimmunity through impairment of dendritic cell maturation and reduction of regulatory T cells.These changes in immune functions could alter the pathogenesis of viral hepatitis and autoimmune liver diseases,as well as the development of hepatocellular carcinoma.Moreover,elderly patients have significantly decreased reserve functions of various organs,reducing their tolerability to treatments for liver diseases.Collectively,aged patients show various changes of the liver and other organs that could affect the clinical characteristics and management of liver diseases in these patients.     

Ikterus nach Reisen

International travellers have a risk of acquiring diseases, which are not common in their home countries. A change in behaviour during the travel can lead to infection with communicable diseases or the use of toxic substances. This can result in severe liver damage. Undiagnosed diseases like malaria can be lethal. Travellers with signs of liver damage should be checked for common causes but also for rare tropical diseases.     

Cell therapy for liver diseases: current medicine and future promises

Liver diseases are a major health problem worldwide since they usually represent the main causes of death in most countries, causing excessive costs to public health systems. Nowadays, there are no efficient current therapies for most hepatic diseases and liver transplant is infrequent due to the availability of organs, cost and risk of transplant rejection. Therefore, alternative therapies for liver diseases have been developed, including cell-based therapies. Stem cells (SCs) are characterized by their self-renewing capacity, unlimited proliferation and differentiation under certain conditions into tissue- or organ-specific cells with special functions. Cell-based therapies for liver diseases have been successful in experimental models, showing anti-inflammatory, antifibrogenic and regenerative effects. Nowadays, clinical trials using SCs for liver pathologies are increasing in number, and those that have reached publication have achieved favorable effects, encouraging us to think that SCs will have a potential clinical use in a short time.     

Current treatment for liver metastases from colorectal cancer

The liver is the commonest site of distant metastasis of colorectal cancer and nearly half of the patients with colorectal cancer ultimately develop liver involved during the course of their diseases. Surgery is the only therapy that offers the possibility of cure for patients with hepatic metastatic diseases. Five-year survival rates after resection of all detectable liver metastases can be up to 40 %. Unfortunately, only 25 % of patients with colorectal liver metastases are candidates for liver resection, while the others are not amenable to surgical resection. Regional therapies such as radiofrequency ablation and cryotherapy may be offered to patients with isolated unresectable metastases but no extrahepatic diseases. Hepatic artery catheter chemotherapy and chemoembolization and portal vein embolization are often used for the patients with extensive liver metastases but without extrahepatic diseases, which are not suitable for regional ablation. For the patients with metastatic colorectal cancer beyond the liver, systemic chemotherapy is a more appropriate choice. Immunotherapy is also a good option when other therapies are used in combination to enhance the efficacy. Selective internal radiation therapy is a new radiation method which can be used in patients given other routine therapies without effects.     

New insights into liver stem cells

Hepatic progenitor cells are bi-potential stem cells residing in human and animal livers that are able to differentiate towards the hepatocytic and the cholangiocytic lineages. In adult livers, hepatic progenitor cells are quiescent stem cells with a low proliferating rate, representing a reserve compartment that is activated only when the mature epithelial cells of the liver are continuously damaged or inhibited in their replication, or in cases of severe cell loss.Hepatic progenitor cell activation has been described in various acute and chronic liver diseases. Their niche is composed by numerous cells such as Hepatic Stellate Cells, endothelial cells, hepatocytes, cholangiocytes, Kupffer cells, pit cells and inflammatory cells. All these cells, numerous hormones and growth factors could interact and cross-talk with progenitor cells influencing their proliferative and differentiative processes. Hepatic progenitor cells and their niche could represent, in the near future, a target for therapeutic approaches to liver disease based on cell-specific drug delivery systems.Isolation and transplantation of hepatic progenitor cells could represent a new approach for therapy of end-stage chronic liver diseases, as they offer many advantages to transplantation of mature hepatocytes. The possibility of applying stem cell therapy to liver diseases will represent a major goal in this field.     

51例慢性药物性肝病临床及病理分析

目的分析慢性药物性肝病（CDILD）的病因及临床和病理特点,以尽早做出正确诊断与治疗。方法根据服药史、临床表现、血清学指标、病理特点、病程及停药后的治疗效果进行回顾性病例分析。结果 51例CDILD患者平均病程6.5个月,分型以胆汁淤积型为主,常见诱发药物主要是中草药（27.5%）,消化系统药（11.8%）,解热镇痛类药（11.8%）,其中29例CDILD行肝组织活检,病理改变有一定的特征性。51例CDILD患者经住院治疗,治愈32例,好转19例,无恶化或死亡病例。结论 CDILD患者病程较长,以慢性胆汁淤积型为主,常见诱发药物为中草药,病理改变有一定的特征性,预后良好。     

Functional role of chemokines in liver disease models

Chemokines are a class of small cytokine-like molecules that orchestrate immune cell infiltration into the liver in response to acute and chronic injuries. Apart from their chemotactic effect, however, chemokines seem to mediate many other aspects of liver diseases, including a direct activation of stellate cells, the modulation of hepatocyte proliferation and angiogenesis. The identification of specific biological functions for chemokines in liver diseases has been hampered by the finding that resident and infiltrating cells in the liver are often a source, as well as a target, of chemokines. Furthermore, chemokines might cause differing effects depending on the etiology of liver damage, their local concentrations and their ability to form multimers and heterodimers. Nevertheless, the functions of a number of important chemokines and their associated receptors have been identified in both in vivo and in vitro studies. Indeed, harmful (proinflammatory, profibrogenic) and beneficial (antifibrogenic, antiangiogenic) effects of chemokines have been discovered in experimental liver disease models. In this Review, the current knowledge of chemokines in experimental liver disease models is summarized. Advances that might lead to preclinical applications are discussed, as are the roles of chemokine receptors as promising pharmacologically targetable molecules.     

Endoplasmic reticulum stress and angiogenesis: is there an interaction between them?

When cells are subjected to stress by changes in their extracellular environment, unfolded proteins accumulate in the endoplasmic reticulum (ER), causing ER stress. This initiates the unfolded protein response (UPR), a signal transduction cascade aiming at restoring cellular homeostasis. The UPR and angiogenesis are involved in the pathogenesis of many diseases such as cancer, pulmonary diseases and chronic liver diseases (CLDs) including alcoholic liver disease, non‐alcoholic steatohepatitis and hepatitis B. This review summarizes the upcoming knowledge of the interaction between the UPR and angiogenesis in physiological angiogenesis and in different CLDs and other diseases.     

Caring for adults with pediatric liver disease

The etiology of liver disease in childhood varies significantly from its etiology in the adult population. More children with complex diseases are surviving into adulthood, providing challenges to the primary care provider. Adults with pediatric liver disease differ in management, treatment, complications, and extrahepatic considerations. To provide these patients with an optimal transition into the adult health care system, the provider needs a comprehensive knowledge of the common causes of childhood liver disease and their implications and must understand the differences in caring for these patients. This review addresses some of the most common childhood liver diseases, their causes, presentation, evaluation, management, complications, and additional concerns.     

Autoimmune liver diseases

The liver was one of the earliest recognized sites among autoimmune diseases yet autoimmune hepatitis,primary biliary cirrhosis,primary sclerosing cholangitis,and their overlap forms,are still problematic in diagnosis and causation.The contributions herein comprise ＇pairs of articles＇ on clinical characteristics,and concepts of etiopathogenesis,for each of the above diseases,together with childhood autoimmune liver disease,overlaps,interpretations of diagnostic serology,and liver transplantation.This issue is timely,since we are witnessing an ever increasing applicability of immunology to a wide variety of chronic diseases,hepatic and non-hepatic,in both developed and developing countries.The 11 invited expert review articles capture the changing features over recent years of the autoimmune liver diseases,the underlying immunomolecular mechanisms of development,the potent albeit still unexplained genetic influences,the expanding repertoire of immunoserological diagnostic markers,and the increasingly effective therapeutic possibilities.