Reversibility and heritability of liver fibrosis:Implications for research and therapy

Liver fibrosis continues to be a major health problem worldwide due to lack of effective therapy.If the etiology cannot be eliminated,liver fibrosis progresses to cirrhosis and eventually to liver failure or malignancy;both are associated with a fatal outcome.Liver transplantation,the only curative therapy,is still mostly unavailable.Liver fibrosis was shown to be a reversible process;however,complete reversibility remains debatable.Recently,the molecular markers of liver fibrosis were shown to be transmitted across generations.Epigenetic mechanisms including DNA methylation,histone posttranslational modifications and noncoding RNA have emerged as major determinants of gene expression during liver fibrogenesis and carcinogenesis.Furthermore,epigenetic mechanisms have been shown to be transmitted through mitosis and meiosis to daughter cells and subsequent generations.However,the exact epigenetic regulation of complete liver fibrosis resolution and inheritance has not been fully elucidated.This communication will highlight the recent advances in the search for delineating the mechanisms governing resolution of liver fibrosis and the potential for multigenerational and transgenerational transmission of fibrosis markers.The fact that epigenetic changes,unlike genetic mutations,are reversible and can be modulated pharmacologically underscores the unique opportunity to develop effective therapy to completely reverse liver fibrosis,to prevent the development of malignancy and to regulate heritability of fibrosis phenotype.

Hepatic stem cells: A viable approach for the treatment of liver cirrhosis

Liver cirrhosis is characterized by distortion of liver architecture, necrosis of hepatocytes and regenerative nodules formation leading to cirrhosis. Various types of cell sources have been used for the management and treatment of decompensated liver cirrhosis.Knowledge of stem cells has offered a new dimension for regenerative therapy and has been considered as one of the potential adjuvant treatment modality in patients with end stage liver diseases(ESLD). Human fetal hepatic progenitor cells are less immunogenic than adult ones. They are highly propagative and challenging to cryopreservation. In our earlier studies we have demonstrated that fetuses at 10-18 wk of gestation age contain a large number of actively dividing hepatic stem and progenitor cells which possess bipotent nature having potential to differentiate into bile duct cells and mature hepatocytes. Hepatic stem cell therapy for the treatment of ESLD is in their early stage of the translation. The emerging technology of decellularization and recellularization might offer a significant platform for developing bioengineered personalized livers to come over the scarcity of desired number of donor organs for the treatment of ESLD. Despite these significant advancements long-term tracking of stem cells in human is the most important subject nowadays in order to answer several unsettles issues regarding the route of delivery, the choice of stem cell type(s), the cell number and the timepoint of cell delivery for the treatment in a chronic setting. Answering to these questions will further contribute to the development of safer, noninvasive, and repeatable imaging modalities that could discover better cell therapeutic approaches from bench to bedside. Combinatorial approach of decellularization and nanotechnology could pave a way towards the better understanding in determination of cell fate posttransplantation.

Endoscopic submucosal dissection in early gastric cancer in elderly patients and comorbid conditions

The prognosis of early gastric cancer(EGC) is good if there is no concomitant lymph node metastasis. Therefore, the early detection of EGC is important to improve the prognosis of patients with gastric cancer. In Japan, 40% to 50% of all gastric cancers are EGC, and endoscopic submucosal dissection(ESD) is widely accepted as a local treatment for these lesions, particularly for large lesions that at one time were an indication for gastrectomy because of the difficulty of en-bloc resection. Consequently, this procedure can preserve the entire stomach and the patient's postoperative quality of life. ESD has become a general technique with improved procedures and devices, and has become the preferred treatment for EGC rather than gastrectomy. Therefore, ESD may demonstrate many advantages in patients who have several comorbidities, particularly elderly population, patients taking antithrombotic agents, or patients with chronic kidney disease, or liver cirrhosis. However, it is not yet clear whether patients with both EGC and comorbidities are feasible candidates for ESD and whether they would consequently be able to achieve a survival benefit after ESD. In this review, we discuss the clinical problems of ESD in patients with EGC and those comorbid conditions.

Management of rectal varices in portal hypertension

Rectal varices are portosystemic collaterals that form as a complication of portal hypertension, their prevalence has been reported as high as 94% in patients withextrahepatic portal vein obstruction. The diagnosis is typically based on lower endoscopy(colonoscopy or sigmoidoscopy). However, endoscopic ultrasonography has been shown to be superior to endoscopy in diagnosing rectal varices. Color Doppler ultrasonography is a better method because it allows the calculation of the velocity of blood flow in the varices and can be used to predict the bleeding risk in the varices. Although rare, bleeding from rectal varices can be life threatening. The management of patients with rectal variceal bleeding is not well established. It is important to ensure hemodynamic stability with blood transfusion and to correct any coagulopathy prior to treating the bleeding varices. Endoscopic injection sclerotherapy has been reported to be more effective in the management of active bleeding from rectal varices with less rebleeding rate as compared to endoscopic band ligation. Transjugular intrahepatic portsystemic shunt alone or in combination with embolization is another method used successfully in control of bleeding. Balloon-occluded retrograde transvenous obliteration is an emerging procedure for management of gastric varices that has also been successfully used to treat bleeding rectal varices. Surgical procedures including suture ligation and porto-caval shunts are considered when other methods have failed.

Traditional Chinese medicine for treatment of liver diseases: progress, challenges and opportunities

Traditional Chinese medicine （TCM） is commonly used in treating liver diseases worldwide, especially in China. The advantages of using TCM for treatment of liver diseases include： protecting hepatocytes, inhibiting hepatic inflammation and antifibrosis in the liver. In this article, we introduce TCM herbal preparations from the Chinese materia medica （such as Fuzheng Huayu） that are typically used for the treatment of liver diseases. Literature surrounding the mechanisms of TCM therapy for treatment of liver diseases is presented and discussed. We propose that side effects of herbal compounds are often under-appreciated, and that more care should be taken in the prescription of potentially hepatotoxic medicines. Further, to deepen the understanding of TCM mechanisms, new techniques and methodologies must be developed. Future studies will lead to the enhancement of clinical outcomes of TCM. As complementary and alternative therapies, TCMs will play an expanding role in the future of liver disease treatment.