Pub Date : 2020-03-24eCollection Date: 2020-01-01DOI: 10.2147/HMER.S232392
Narong Khuntikeo, Attapol Titapun, Nittaya Chamadol, Wuttisak Boonphongsathien, Prakasit Sa-Ngiamwibool, Simon D Taylor-Robinson, Christopher A Wadsworth, Shuo Zhang, Evdokia M Kardoulaki, Ian R Young, Richard R A Syms
Aim: Cholangiocarcinoma is endemic in southeast Asia, generally developing from liver fluke infestation. However, diagnostic imaging of early-stage disease is challenging. The aim of this work is to investigate relaxometry (specifically, T2 mapping) as a method of exploiting the higher signal-to-noise ratio (SNR) of internal coils for improved reception of magnetic resonance signals, despite their non-uniform sensitivity.
Methods: Ex vivo T2 mapping was carried out at 3T on fixed resection specimens from Thai cholangiocarcinoma patients using an mGRASE sequence and an endoscope coil based on a thin-film magneto-inductive waveguide and designed ultimately for internal use.
Results: Disease-induced changes including granulomatous inflammation, intraepithelial neoplasia and intraductal tumours were correlated with histopathology, and relaxation data were compared with mono- and bi-exponential models of T2 relaxation. An approximately 10-fold local advantage in SNR compared to a 16-element torso coil was demonstrated using the endoscope coil, and improved tissue differentiation was obtained without contrast agents.
Conclusion: The performance advantage above follows directly from the inverse relation between the component of the standard deviation of T2 due to thermal noise and the SNR, and offers an effective method of exploiting the SNR advantage of internal coils. No correction is required, avoiding the need for tracking, relaxing constraints on coil and slice orientation and providing rapid visualization.
{"title":"Improving the Detection of Cholangiocarcinoma: In vitro MRI-Based Study Using Local Coils and T2 Mapping.","authors":"Narong Khuntikeo, Attapol Titapun, Nittaya Chamadol, Wuttisak Boonphongsathien, Prakasit Sa-Ngiamwibool, Simon D Taylor-Robinson, Christopher A Wadsworth, Shuo Zhang, Evdokia M Kardoulaki, Ian R Young, Richard R A Syms","doi":"10.2147/HMER.S232392","DOIUrl":"https://doi.org/10.2147/HMER.S232392","url":null,"abstract":"<p><strong>Aim: </strong>Cholangiocarcinoma is endemic in southeast Asia, generally developing from liver fluke infestation. However, diagnostic imaging of early-stage disease is challenging. The aim of this work is to investigate relaxometry (specifically, T2 mapping) as a method of exploiting the higher signal-to-noise ratio (SNR) of internal coils for improved reception of magnetic resonance signals, despite their non-uniform sensitivity.</p><p><strong>Methods: </strong>Ex vivo T2 mapping was carried out at 3T on fixed resection specimens from Thai cholangiocarcinoma patients using an mGRASE sequence and an endoscope coil based on a thin-film magneto-inductive waveguide and designed ultimately for internal use.</p><p><strong>Results: </strong>Disease-induced changes including granulomatous inflammation, intraepithelial neoplasia and intraductal tumours were correlated with histopathology, and relaxation data were compared with mono- and bi-exponential models of T2 relaxation. An approximately 10-fold local advantage in SNR compared to a 16-element torso coil was demonstrated using the endoscope coil, and improved tissue differentiation was obtained without contrast agents.</p><p><strong>Conclusion: </strong>The performance advantage above follows directly from the inverse relation between the component of the standard deviation of T2 due to thermal noise and the SNR, and offers an effective method of exploiting the SNR advantage of internal coils. No correction is required, avoiding the need for tracking, relaxing constraints on coil and slice orientation and providing rapid visualization.</p>","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2020-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S232392","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37826864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-02-13eCollection Date: 2020-01-01DOI: 10.2147/HMER.S243277
Rajagopal N Aravalli, Daniel P Collins, Joel H Hapke, Andrew T Crane, Clifford J Steer
Background: Primary human hepatocytes (PHHs) are the ideal candidates for studying critical liver functions such as drug metabolism and toxicity. However, as they are isolated from discarded livers that are unsuitable for transplantation, they possess limited expansion ability invitro and their enzymatic functions deteriorate rapidly because they are often of poor quality. Therefore, there is a compelling reason to find reliable alternative sources of hepatocytes.
Methods: In this study, we report on efficient and robust differentiation of embryonic stem cells (ESC) from the common marmoset Callithrix jacchus into functional hepatocyte-like cells (HLC) using a simple, and reproducible three-step procedure. ESC-derived HLCs were examined by morphological analysis and tested for their expression of hepatocyte-specific markers using a combination of immunohistochemistry, RT-PCR, and biochemical assays. Primary human hepatocytes were used as controls.
Results: ESC-derived HLCs expressed each of the hepatocyte-specific markers tested, including albumin; α-fetoprotein; asialoglycoprotein receptor 1; α-1 antitrypsin; hepatocyte nuclear factors 1α and 4; cytokeratin 18; hepatocyte growth factor receptor; transferrin; tyrosine aminotransferase; alkaline phosphatase; c-reactive protein; cytochrome P450 enzymes CYP1A2, CYP2E1 and CYP3A4; and coagulation factors FVII and FIX. They were functionally competent as demonstrated by biochemical assays in addition to producing urea.
Conclusion: Our data strongly suggest that marmoset HLCs possess characteristics similar to those of PHHs. They could, therefore, be invaluable for studies on drug metabolism and cell transplantation therapy for a variety of liver disorders. Because of the similarities in the anatomical and physiological features of the common marmoset to that of humans, Callithrix jacchus is an appropriate animal model to study human disease conditions and cellular functions.
{"title":"Hepatic Differentiation of Marmoset Embryonic Stem Cells and Functional Characterization of ESC-Derived Hepatocyte-Like Cells.","authors":"Rajagopal N Aravalli, Daniel P Collins, Joel H Hapke, Andrew T Crane, Clifford J Steer","doi":"10.2147/HMER.S243277","DOIUrl":"https://doi.org/10.2147/HMER.S243277","url":null,"abstract":"<p><strong>Background: </strong>Primary human hepatocytes (PHHs) are the ideal candidates for studying critical liver functions such as drug metabolism and toxicity. However, as they are isolated from discarded livers that are unsuitable for transplantation, they possess limited expansion ability <i>in</i> <i>vitro</i> and their enzymatic functions deteriorate rapidly because they are often of poor quality. Therefore, there is a compelling reason to find reliable alternative sources of hepatocytes.</p><p><strong>Methods: </strong>In this study, we report on efficient and robust differentiation of embryonic stem cells (ESC) from the common marmoset <i>Callithrix jacchus</i> into functional hepatocyte-like cells (HLC) using a simple, and reproducible three-step procedure. ESC-derived HLCs were examined by morphological analysis and tested for their expression of hepatocyte-specific markers using a combination of immunohistochemistry, RT-PCR, and biochemical assays. Primary human hepatocytes were used as controls.</p><p><strong>Results: </strong>ESC-derived HLCs expressed each of the hepatocyte-specific markers tested, including albumin; α-fetoprotein; asialoglycoprotein receptor 1; α-1 antitrypsin; hepatocyte nuclear factors 1α and 4; cytokeratin 18; hepatocyte growth factor receptor; transferrin; tyrosine aminotransferase; alkaline phosphatase; c-reactive protein; cytochrome P450 enzymes CYP1A2, CYP2E1 and CYP3A4; and coagulation factors FVII and FIX. They were functionally competent as demonstrated by biochemical assays in addition to producing urea.</p><p><strong>Conclusion: </strong>Our data strongly suggest that marmoset HLCs possess characteristics similar to those of PHHs. They could, therefore, be invaluable for studies on drug metabolism and cell transplantation therapy for a variety of liver disorders. Because of the similarities in the anatomical and physiological features of the common marmoset to that of humans, <i>Callithrix jacchus</i> is an appropriate animal model to study human disease conditions and cellular functions.</p>","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2020-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S243277","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37682054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advances in imaging, pathology and therapy have resulted in major improvements in the management of cholangiocarcinomas; the mortality has come down and with it there has been an improved 5-year survival. Surgical resection remains the treatment of choice and reports from high volume centres have shown an increase in resectability rates, R0 resection, a decrease in mortality and an improvement in 5-year survival; however, the operative morbidity remains high, pointing towards the complexity of the management of these difficult lesions. Complete excision is also often limited by the locally advanced nature of the disease at the time of diagnosis and a proportion of patients who were earlier deemed resectable on imaging are found to have unresectable disease at the time of operation. Neoadjuvant therapy has had only a limited impact on survival. Liver transplantation is also an option in a few patients following strict criteria for selection. Since the large majority of patients are only diagnosed at the late stages of the disease palliation (endoscopic or surgical) is an important part of treatment. Portal vein embolisation and pre-operative biliary drainage have had a major impact on outcomes. Major liver resection with caudate lobe removal remains the standard operation and procedures like routine vascular resection and liver transplant should only be carried out in experienced centres. Improvements in both neo as well as adjuvant therapy may lead to a standardized protocol in the future, as well as an improvement in survival.
{"title":"Management Strategies for Patients with Hilar Cholangiocarcinomas: Challenges and Solutions.","authors":"Siddharth Mehrotra, Shailendra Lalwani, Samiran Nundy","doi":"10.2147/HMER.S223022","DOIUrl":"https://doi.org/10.2147/HMER.S223022","url":null,"abstract":"<p><p>Advances in imaging, pathology and therapy have resulted in major improvements in the management of cholangiocarcinomas; the mortality has come down and with it there has been an improved 5-year survival. Surgical resection remains the treatment of choice and reports from high volume centres have shown an increase in resectability rates, R0 resection, a decrease in mortality and an improvement in 5-year survival; however, the operative morbidity remains high, pointing towards the complexity of the management of these difficult lesions. Complete excision is also often limited by the locally advanced nature of the disease at the time of diagnosis and a proportion of patients who were earlier deemed resectable on imaging are found to have unresectable disease at the time of operation. Neoadjuvant therapy has had only a limited impact on survival. Liver transplantation is also an option in a few patients following strict criteria for selection. Since the large majority of patients are only diagnosed at the late stages of the disease palliation (endoscopic or surgical) is an important part of treatment. Portal vein embolisation and pre-operative biliary drainage have had a major impact on outcomes. Major liver resection with caudate lobe removal remains the standard operation and procedures like routine vascular resection and liver transplant should only be carried out in experienced centres. Improvements in both neo as well as adjuvant therapy may lead to a standardized protocol in the future, as well as an improvement in survival.</p>","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2020-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S223022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37726458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the West. Non-alcoholic steatohepatitis (NASH) is the progressive form of NAFLD and can lead to cirrhosis, hepatocellular carcinoma, and is associated with increased cardiovascular risks. Multiple components and risk factors are thought to be involved in the pathogenesis of NAFLD and NASH. Optimal therapy has not yet been found, but many advances have been made with the discovery of potential therapeutic options. In this paper, we aim to provide a comprehensive review of approved, studied, and upcoming treatment options for NAFLD and NASH. Non-pharmacologic therapy (lifestyle modifications and bariatric surgery) and pharmacologic therapy are both reviewed. Pharmacologic therapy target components thought to be involved in the pathogenesis of this disease process including insulin resistance, oxidative stress, inflammation, lipid metabolism, and fibrosis are reviewed in this paper. Results of the emerging treatment targets in phase 2 and 3 clinical trials are also included.
{"title":"A Review Of Current And Upcoming Treatment Modalities In Non-Alcoholic Fatty Liver Disease And Non-Alcoholic Steatohepatitis","authors":"S. Ganguli, P. Deleeuw, S. Satapathy","doi":"10.2147/HMER.S188991","DOIUrl":"https://doi.org/10.2147/HMER.S188991","url":null,"abstract":"Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the West. Non-alcoholic steatohepatitis (NASH) is the progressive form of NAFLD and can lead to cirrhosis, hepatocellular carcinoma, and is associated with increased cardiovascular risks. Multiple components and risk factors are thought to be involved in the pathogenesis of NAFLD and NASH. Optimal therapy has not yet been found, but many advances have been made with the discovery of potential therapeutic options. In this paper, we aim to provide a comprehensive review of approved, studied, and upcoming treatment options for NAFLD and NASH. Non-pharmacologic therapy (lifestyle modifications and bariatric surgery) and pharmacologic therapy are both reviewed. Pharmacologic therapy target components thought to be involved in the pathogenesis of this disease process including insulin resistance, oxidative stress, inflammation, lipid metabolism, and fibrosis are reviewed in this paper. Results of the emerging treatment targets in phase 2 and 3 clinical trials are also included.","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2019-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S188991","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45940271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ghodsiyeh Azarkar, Z. Doosti, Freshteh Osmani, M. Ziaee
Background Nonalcoholic fatty-liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Although NAFLD has been studied extensively, potential risk factors for NAFLD among chronic hepatitis B (CHB) patients and their comparison with healthy individuals have remained understudied in Iran. As such, we examined the association between HBV infection and the development of NAFLD in two groups. Methods A case–control study was done on 376 CHB patients and 447 healthy subjects randomly selected from Birjand, South Khorasan province, Iran. We used logistic regression to estimate adjusted ORs with 95% CIs for incidence of NAFLD. Potential risk factors for NAFLD were evaluated while adjusting for age, sex, marital status, and educational level. Also, χ2 was used to compare demographic characteristics between the two groups. Results A total of 373 CHB patients (mean age 40.1±12.9 years) versus 447 individuals in the control group (mean age 39.8±13.9 years) were included in this study (p=0.337). Liver characteristics were found to be significantly different in CHB and healthy groups (p<0.05). According to the results obtained from logistic regression, the adjusted OR (95% CI) for NAFLD incidence of comparing HBsAg-positive to HBsAg-negative participants was 0.62 (0.45–0.84). Conclusion The results suggested that HBsAg seropositivity was associated with lower risk of developing NAFLD. This study also revealed that mild cases of fatty liver in carriers of hepatitis B are more common than in healthy subjects. However, moderate and severe cases of this condition are more common in healthy people than in hepatitis B carriers.
{"title":"Analysis Of Risk Factors For Nonalcoholic Fatty-Liver Disease In Hepatitis B Virus Infection: A Case–Control Study","authors":"Ghodsiyeh Azarkar, Z. Doosti, Freshteh Osmani, M. Ziaee","doi":"10.2147/HMER.S211106","DOIUrl":"https://doi.org/10.2147/HMER.S211106","url":null,"abstract":"Background Nonalcoholic fatty-liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Although NAFLD has been studied extensively, potential risk factors for NAFLD among chronic hepatitis B (CHB) patients and their comparison with healthy individuals have remained understudied in Iran. As such, we examined the association between HBV infection and the development of NAFLD in two groups. Methods A case–control study was done on 376 CHB patients and 447 healthy subjects randomly selected from Birjand, South Khorasan province, Iran. We used logistic regression to estimate adjusted ORs with 95% CIs for incidence of NAFLD. Potential risk factors for NAFLD were evaluated while adjusting for age, sex, marital status, and educational level. Also, χ2 was used to compare demographic characteristics between the two groups. Results A total of 373 CHB patients (mean age 40.1±12.9 years) versus 447 individuals in the control group (mean age 39.8±13.9 years) were included in this study (p=0.337). Liver characteristics were found to be significantly different in CHB and healthy groups (p<0.05). According to the results obtained from logistic regression, the adjusted OR (95% CI) for NAFLD incidence of comparing HBsAg-positive to HBsAg-negative participants was 0.62 (0.45–0.84). Conclusion The results suggested that HBsAg seropositivity was associated with lower risk of developing NAFLD. This study also revealed that mild cases of fatty liver in carriers of hepatitis B are more common than in healthy subjects. However, moderate and severe cases of this condition are more common in healthy people than in hepatitis B carriers.","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2019-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S211106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44616089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Page, F. Qeadan, C. Qualls, K. Thornton, Sanjeev Arora
Abstract Propensity score analysis is a statistical approach to reduce bias often present in non-randomized observational studies. In this paper we use this method to re-analyze data from a study that assessed whether patients receiving HCV treatment from providers in Project ECHO had different clinical outcomes than patients treated by specialists from an academic medical center (UNM HCV clinic) but in which treatment assignment was not randomized. We modeled the best estimated probability of treatment assignment, and then assess differences overall SVR and SVR in patients with genotype 1 infection by treatment arm using Stabilized Inverse Probability of Treatment Weights (SIPTW). Results show that after adjustment for SIPTW, HCV treatment outcomes were significantly better for the ECHO patients compared to the UNM HCV clinic patients. Higher proportions of patients treated by primary care providers achieved SVR and SVR with genotype 1 compared to those treated at UNM HCV clinic with 15.1% and 16.3% absolute differences, respectively. These results indicate that previously published results (showing no differences) were biased, and resulted in an underestimation of the treatment effect of ECHO on HCV treatment.
{"title":"Project ECHO Revisited: Propensity Score Analysis And HCV Treatment Outcomes","authors":"K. Page, F. Qeadan, C. Qualls, K. Thornton, Sanjeev Arora","doi":"10.2147/HMER.S212855","DOIUrl":"https://doi.org/10.2147/HMER.S212855","url":null,"abstract":"Abstract Propensity score analysis is a statistical approach to reduce bias often present in non-randomized observational studies. In this paper we use this method to re-analyze data from a study that assessed whether patients receiving HCV treatment from providers in Project ECHO had different clinical outcomes than patients treated by specialists from an academic medical center (UNM HCV clinic) but in which treatment assignment was not randomized. We modeled the best estimated probability of treatment assignment, and then assess differences overall SVR and SVR in patients with genotype 1 infection by treatment arm using Stabilized Inverse Probability of Treatment Weights (SIPTW). Results show that after adjustment for SIPTW, HCV treatment outcomes were significantly better for the ECHO patients compared to the UNM HCV clinic patients. Higher proportions of patients treated by primary care providers achieved SVR and SVR with genotype 1 compared to those treated at UNM HCV clinic with 15.1% and 16.3% absolute differences, respectively. These results indicate that previously published results (showing no differences) were biased, and resulted in an underestimation of the treatment effect of ECHO on HCV treatment.","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S212855","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41881457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Cirrhosis is characterized by extensive hepatic fibrosis, and it is the 14th leading cause of death worldwide. Numerous contributing conditions have been implicated in its development, including infectious etiologies, medication overdose or adverse effects, ingestible toxins, autoimmunity, hemochromatosis, Wilson’s disease and primary biliary cholangitis to list a few. It is associated with portal hypertension and its stigmata (varices, ascites, hepatic encephalopathy, combined coagulopathy and thrombophilia), and it is a major risk factor for hepatocellular carcinoma. Currently, orthotopic liver transplantation has been the only curative modality to treat cirrhosis, and the scarcity of donors results in many people waiting years for a transplant. Identification of novel targets for pharmacologic therapy through elucidation of key mechanistic components to induce fibrosis reversal is the subject of intense research. Development of robust models of hepatic fibrosis to faithfully characterize the interplay between activated hepatic stellate cells (the principal fibrogenic contributor to fibrosis initiation and perpetuation), hepatocytes and extracellular matrix components has the potential to identify critical components and mechanisms that can be exploited for targeted treatment. In this review, we will highlight key cellular pathways involved in the pathophysiology of fibrosis from extracellular ligands, effectors and receptors, to nuclear receptors, epigenetic mechanisms, energy homeostasis and cytokines. Further, molecular pathways of hepatic stellate cell deactivation are discussed, including apoptosis, senescence and reversal or transdifferentiation to an inactivated state resembling quiescence. Lastly, clinical evidence of fibrosis reversal induced by biologics and small molecules is summarized, current compounds under clinical trials are described and efforts for treatment of hepatic fibrosis with mesenchymal stem cells are highlighted. An enhanced understanding of the rich tapestry of cellular processes identified in the initiation, perpetuation and resolution of hepatic fibrosis, driven principally through phenotypic switching of hepatic stellate cells, should lead to a breakthrough in potential therapeutic modalities.
{"title":"“Let my liver rather heat with wine” - a review of hepatic fibrosis pathophysiology and emerging therapeutics","authors":"C. G. Moscoso, C. Steer","doi":"10.2147/HMER.S213397","DOIUrl":"https://doi.org/10.2147/HMER.S213397","url":null,"abstract":"Abstract Cirrhosis is characterized by extensive hepatic fibrosis, and it is the 14th leading cause of death worldwide. Numerous contributing conditions have been implicated in its development, including infectious etiologies, medication overdose or adverse effects, ingestible toxins, autoimmunity, hemochromatosis, Wilson’s disease and primary biliary cholangitis to list a few. It is associated with portal hypertension and its stigmata (varices, ascites, hepatic encephalopathy, combined coagulopathy and thrombophilia), and it is a major risk factor for hepatocellular carcinoma. Currently, orthotopic liver transplantation has been the only curative modality to treat cirrhosis, and the scarcity of donors results in many people waiting years for a transplant. Identification of novel targets for pharmacologic therapy through elucidation of key mechanistic components to induce fibrosis reversal is the subject of intense research. Development of robust models of hepatic fibrosis to faithfully characterize the interplay between activated hepatic stellate cells (the principal fibrogenic contributor to fibrosis initiation and perpetuation), hepatocytes and extracellular matrix components has the potential to identify critical components and mechanisms that can be exploited for targeted treatment. In this review, we will highlight key cellular pathways involved in the pathophysiology of fibrosis from extracellular ligands, effectors and receptors, to nuclear receptors, epigenetic mechanisms, energy homeostasis and cytokines. Further, molecular pathways of hepatic stellate cell deactivation are discussed, including apoptosis, senescence and reversal or transdifferentiation to an inactivated state resembling quiescence. Lastly, clinical evidence of fibrosis reversal induced by biologics and small molecules is summarized, current compounds under clinical trials are described and efforts for treatment of hepatic fibrosis with mesenchymal stem cells are highlighted. An enhanced understanding of the rich tapestry of cellular processes identified in the initiation, perpetuation and resolution of hepatic fibrosis, driven principally through phenotypic switching of hepatic stellate cells, should lead to a breakthrough in potential therapeutic modalities.","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S213397","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43129261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Schistosomiasis is a public health problem in many countries. Its prevalence is increasing annually; the current infection rate is one in 30 individuals. The WHO reported that at least 206.4 million people all over the world required preventive treatments for schistosomiasis in 2016. Chronic schistosomiasis, hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection are common in countries where schistosomiasis is endemic. The effects of the hepatotropic virus co-infection may modify the Th2-dominated granulomatous phase of schistosomal infection. These viruses induce a strong-specific T cell response, with infiltration of large numbers of specific interferon-γ-producing CD8+ cells into the liver. The outcome of liver diseases depends on the underlying causes, host immune response and concomitant infections. Co-infection of schistosomiasis with HBV/HCV infection causes advanced liver disease and worsens the outcome, especially with higher viral load titers, which increase the mortality rate through an increased incidence of liver cirrhosis and hepatocellular carcinoma. The exposure risk for HBV in patients with HCV and schistosomiasis was two and half times greater than that in CHC patients without schistosomiasis. Finally, chronic schistosomiasis and HBV/HCV co-infection have serious effects on liver pathology. Co-infection accelerates the progression of liver disease and leads to advanced liver diseases and liver failure.
{"title":"Impact of chronic schistosomiasis and HBV/HCV co-infection on the liver: current perspectives","authors":"H. Omar","doi":"10.2147/HMER.S155962","DOIUrl":"https://doi.org/10.2147/HMER.S155962","url":null,"abstract":"Abstract Schistosomiasis is a public health problem in many countries. Its prevalence is increasing annually; the current infection rate is one in 30 individuals. The WHO reported that at least 206.4 million people all over the world required preventive treatments for schistosomiasis in 2016. Chronic schistosomiasis, hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection are common in countries where schistosomiasis is endemic. The effects of the hepatotropic virus co-infection may modify the Th2-dominated granulomatous phase of schistosomal infection. These viruses induce a strong-specific T cell response, with infiltration of large numbers of specific interferon-γ-producing CD8+ cells into the liver. The outcome of liver diseases depends on the underlying causes, host immune response and concomitant infections. Co-infection of schistosomiasis with HBV/HCV infection causes advanced liver disease and worsens the outcome, especially with higher viral load titers, which increase the mortality rate through an increased incidence of liver cirrhosis and hepatocellular carcinoma. The exposure risk for HBV in patients with HCV and schistosomiasis was two and half times greater than that in CHC patients without schistosomiasis. Finally, chronic schistosomiasis and HBV/HCV co-infection have serious effects on liver pathology. Co-infection accelerates the progression of liver disease and leads to advanced liver diseases and liver failure.","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S155962","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41547139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abraham Goa, Tadele Dana, Shimelash Bitew, Aseb Kinfe Arba
Background Hepatitis B virus infection (HBV) constitutes major public health problems in sub-Saharan Africa from different infections occuring in HIV positive patients. Ethiopia is a part of sub-Saharan Africa with 1.5% adult HIV prevalence, and also belongs to the intermediate to high HBV prevalence category. Hence, this study aimed to measure the seroprevalence and associated factors of HBV infection among HIV-positive adults attending an antiretroviral treatment (ART) clinic at Wolaita Sodo University Referral Hospital. Methods An institution-based cross-sectional study was conducted from October 15 to December 10, 2017 using a systematic random sampling technique. After getting informed written consent, data were collected by a structured and interviewer-administered questionnaire. Venous blood was collected and centrifuged to separate serum. Hepatitis B surface antigen (HBsAg) was detected from serum using an advanced quality one-step rapid test kit. Data were entered into EpiData version 3.01 and exported to SPSS version 20. Summary statistics, bivariate analysis, and multivariate analyses were performed. The variables having significant association of P<0.05 in the multivariate logistic regression were taken as independent factors. OR and 95% CI were used to measure the strength of the association. Results A total of 442 study participants, 187 males and 255 females, were included in this study. Overall prevalence of HBsAg was 37 (8.4%). Family history of HBV (adjusted OR=8.83, 95% CI=2.56–30.49), multiple sexual partners (adjusted OR=7.08, 95% CI=2.29–21.9), and CD4 count <200 cells/μL (adjusted OR=15.34, 95% CI=4.77–49.3) were found to be significantly associated with HBsAg positivity. Conclusion The prevalence of HBsAg in this study was high. Family history of HBV, multiple sexual partners, and CD4 count <200 cells/μL were independently associated with HBsAg positivity. Therefore, screening for HBV is recommended before initiation of ART in HIV patients and providing appropriate treatment for co-infection. Furthermore, accurate information on risk factors for HBV transmission should be provided.
{"title":"Seroprevalence and associated factors of hepatitis B virus infection among HIV-positive adults attending an antiretroviral treatment clinic at Wolaita Sodo University Referral Hospital","authors":"Abraham Goa, Tadele Dana, Shimelash Bitew, Aseb Kinfe Arba","doi":"10.2147/HMER.S206870","DOIUrl":"https://doi.org/10.2147/HMER.S206870","url":null,"abstract":"Background Hepatitis B virus infection (HBV) constitutes major public health problems in sub-Saharan Africa from different infections occuring in HIV positive patients. Ethiopia is a part of sub-Saharan Africa with 1.5% adult HIV prevalence, and also belongs to the intermediate to high HBV prevalence category. Hence, this study aimed to measure the seroprevalence and associated factors of HBV infection among HIV-positive adults attending an antiretroviral treatment (ART) clinic at Wolaita Sodo University Referral Hospital. Methods An institution-based cross-sectional study was conducted from October 15 to December 10, 2017 using a systematic random sampling technique. After getting informed written consent, data were collected by a structured and interviewer-administered questionnaire. Venous blood was collected and centrifuged to separate serum. Hepatitis B surface antigen (HBsAg) was detected from serum using an advanced quality one-step rapid test kit. Data were entered into EpiData version 3.01 and exported to SPSS version 20. Summary statistics, bivariate analysis, and multivariate analyses were performed. The variables having significant association of P<0.05 in the multivariate logistic regression were taken as independent factors. OR and 95% CI were used to measure the strength of the association. Results A total of 442 study participants, 187 males and 255 females, were included in this study. Overall prevalence of HBsAg was 37 (8.4%). Family history of HBV (adjusted OR=8.83, 95% CI=2.56–30.49), multiple sexual partners (adjusted OR=7.08, 95% CI=2.29–21.9), and CD4 count <200 cells/μL (adjusted OR=15.34, 95% CI=4.77–49.3) were found to be significantly associated with HBsAg positivity. Conclusion The prevalence of HBsAg in this study was high. Family history of HBV, multiple sexual partners, and CD4 count <200 cells/μL were independently associated with HBsAg positivity. Therefore, screening for HBV is recommended before initiation of ART in HIV patients and providing appropriate treatment for co-infection. Furthermore, accurate information on risk factors for HBV transmission should be provided.","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S206870","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46568682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Philips, P. Augustine, Praveen Kumar Yerol, S. Rajesh, P. Mahadevan
Abstract Severe acute alcoholic hepatitis (AH) is a catastrophic disease in the natural history of alcoholic liver disease with a very high 180-day mortality. It can present as acute on chronic liver failure with worse prognosis in the presence of infections and higher grades of liver disease severity. The clinical scenario involves a patient with a recent history of heavy alcohol consumption within three months of presentation with jaundice and characteristic liver enzyme elevation pattern with coagulopathy, hepatic encephalopathy, variceal bleeding and sepsis that results in extrahepatic organ failures. Several liver disease severities and therapy response indicators are in clinical use. Even though not approved, the only recommended treatment option for patients with severe AH is corticosteroids, which is without long term survival benefit. Novel efficacious treatment options awaiting high-quality multi-center studies include liver transplantation (involves strict selection criteria), growth factor therapy and fecal microbiota transplantation. In this exhaustive review, we discuss the definitions, disease severity, histopathology, and treatment options – past, present, and future, in patients with severe alcoholic hepatitis.
{"title":"Severe alcoholic hepatitis: current perspectives","authors":"C. Philips, P. Augustine, Praveen Kumar Yerol, S. Rajesh, P. Mahadevan","doi":"10.2147/HMER.S197933","DOIUrl":"https://doi.org/10.2147/HMER.S197933","url":null,"abstract":"Abstract Severe acute alcoholic hepatitis (AH) is a catastrophic disease in the natural history of alcoholic liver disease with a very high 180-day mortality. It can present as acute on chronic liver failure with worse prognosis in the presence of infections and higher grades of liver disease severity. The clinical scenario involves a patient with a recent history of heavy alcohol consumption within three months of presentation with jaundice and characteristic liver enzyme elevation pattern with coagulopathy, hepatic encephalopathy, variceal bleeding and sepsis that results in extrahepatic organ failures. Several liver disease severities and therapy response indicators are in clinical use. Even though not approved, the only recommended treatment option for patients with severe AH is corticosteroids, which is without long term survival benefit. Novel efficacious treatment options awaiting high-quality multi-center studies include liver transplantation (involves strict selection criteria), growth factor therapy and fecal microbiota transplantation. In this exhaustive review, we discuss the definitions, disease severity, histopathology, and treatment options – past, present, and future, in patients with severe alcoholic hepatitis.","PeriodicalId":12917,"journal":{"name":"Hepatic Medicine : Evidence and Research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2019-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HMER.S197933","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49271426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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