Chronic liver disease (CLD) is an under-recognized epidemic that continues to increase in prevalence and is a major health concern. Silymarin, the active compound of Silybum marianum (Milk thistle), has historically been used in CLD. A significant barrier to silymarin use is its poor bioavailability. Attempts at improving the bioavailability of silymarin have led to a better understanding of formulation methods, pharmacokinetics, dosing, and associated drug interactions. Clinically, silymarin exerts its hepatoprotective effects through antioxidative, antifibrotic, anti-inflammatory, antitoxin, and anticancerous mechanisms of actions. Despite the use of silymarin being extensively studied in alcoholic liver disease, metabolic-associated fatty liver disease, viral hepatitis, and drug-induced liver injury, the overall efficacy of silymarin remains unclear and more research is warranted to better elucidate the role of silymarin in CLD, specifically regarding its anti-inflammatory effects. Here, we review the current biochemical and clinical evidence regarding silymarin in CLD.

Background and Aims: Long-term data on cell-based therapies, including hematopoietic stem cell infusion in cirrhosis, are sparse and lacking.

Methods: Patients with cirrhosis of non-viral etiology received either standard-of-care (n = 23) or autologous CD34+ cell infusion through the hepatic artery (n = 22). Study patients received granulocyte colony-stimulating factor (commonly known as G-CSF) injections at 520 µgm per day for 3 days, followed by leukapheresis and CD34+ cell infusion into the hepatic artery. The Control group received standard-of-care treatment.

Results: Mean CD34+ cell count on the third day of G-CSF injection was 27.00 ± 20.43 cells/µL 81.84 ± 11.99 viability and purity of 80-90%. Significant improvement in the model of end-stage liver disease (commonly known as MELD) score (15.75 ± 5.13 vs. 19.94 ± 6.68, p = 0.04) was noted at end of 3 months and 1 year (15.5 ± 5.3 vs. 19.8 ± 6.4, p = 0.04) but was not statistically different at end of the second (17.2 ± 5.5 vs. 20.3 ± 6.8, p = 0.17) and third-year (18.4 ± 6.1 vs. 21.3 ± 6.4, p = 0.25). No difference in mortality (6/23 vs. 5/23) was noted.

Conclusions: Autologous CD34+ cell infusion effectively improved liver function and MELD score up to 1 year but the sustained benefit was not maintained at the end of 3 years, possibly due to ongoing progression of the underlying disease.

Background and Aims: Coronary artery disease (CAD) is a major cause of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that TCF7L2 rs7903146 was related to the risk of developing NAFLD but the conclusions are not consistent and no related study has been conducted in Chinese populations. The aim of this study was to investigate the association between TCF7L2 rs7903146 and the risk of developing NAFLD and CAD in a Chinese Han population.

Methods:TCF7L2 rs7903146 genotypes were measured by the MALDI-TOF-MS from 143 NAFLD patients, 159 CAD patients, 131 NAFLD + CAD patients, and 212 healthy controls. The demographic data and serum lipid profiles of all subjects were collected. The distributions of genotype and allele frequency in each group were also tested. Logistic regression was used to investigate the risk of TCF7L2 rs7903146 with NAFLD and CAD. All statistical analyses were conducted using SPSS 23.0.

Results: There were no significant differences in the distributions of TCF7L2 rs7903146 genotype and allele frequency in each of the two groups, and the TCF7L2 rs7903146 CT + TT genotype did not increase the risk of developing NAFLD, CAD, and NAFLD + CAD. Except for body mass index in the control group, the differences of clinical parameters between the TCF7L2 rs7903146 T allele carriers and non-carriers in each group were not significant. In the non-obese group, the TCF7L2 rs7903146 CT + TT genotype was a protective factor for the development of NAFLD in the non-obese subjects (odds ratio=0.359, 95% confidence interval: 0.134-0.961, p = 0.041).

Conclusions:TCF7L2 rs7903146 was not associated with the risk of developing NAFLD, CAD, and NAFLD + CAD in the Chinese Han population. In the non-obese population, the TCF7L2 rs7903146 CT + TT genotype was a protective factor against the development of NAFLD.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induced a worldwide pandemic. The main clinical manifestations of COVID-19 patients have been fever, cough, dyspnea, and other respiratory symptoms. However, some patients’ initial symptoms have been nausea, vomiting, diarrhea and other gastrointestinal symptoms, and SARS-CoV-2 RNA could be found in their stool samples. Studies have shown that the gastrointestinal tract highly-expressed angiotensin-converting enzyme 2 is used by SARS-CoV-2 to enter cells. Therefore, exploring the damage caused by SARS-CoV-2 to the gastrointestinal tract and whether it could replicate in the gastrointestinal tract and transmit through fecal-oral route has significance for the diagnosis, treatment and prevention of COVID-19. We combined the current clinical data about COVID-19 patients with gastrointestinal symptoms as well as its pathogenic mechanism and prevention methods herein to review the relationship between the disease and gastrointestinal symptoms.

The severe acute respiratory syndrome corona virus-2 (referred to as SARS CoV2) pandemic had a great impact on public life in general as well as on populations with pre-existing disease and co-morbidities. Liver transplant and immunosuppressant medication predisposes to more severe disease and is often associated with poor outcome. The clinical features, disease course, treatment and process of modulating the immunosuppression is challenging. Here, we describe the clinical presentation, treatment and outcomes in six liver transplant recipients. Out of those six patients, three had mild, one had moderate and one had severe COVID-19, and one was asymptomatic. The immunosuppression minimization or withdrawal was done based upon the clinical severity. Consideration of tocilizumab and/o convalescent plasma as well as antivirals i.e. remdesvir done in severe cases. The routine practice of prophylactic anticoagulation, consideration of repurposed drugs (i.e. teicoplanin and doxycycline), and watchful monitoring of asymptomatic recipients helped to achieve an uneventful recovery.

Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disease of the neuromuscular system and is the most serious type of muscular dystrophy in humans. The disease is characterized by progressive muscular atrophy and a poor prognosis. The incidence rate is 1/3500, and symptoms appear at age of 5 years-old. Some patients present with abnormal aminotransferases as the first symptom. In addition to the clinical characteristics and genetic history, electromyography examination, muscle biopsy, serum enzyme examination, and measures of creatine kinase (CK), CK isoenzyme, and serum lactate dehydrogenase are important features of auxiliary examination. Clinicians who encounter unknown causes of transaminitis should consider the possibility of DMD. We describe here a 3 year-old pediatric patient with increased aminotransferases who had elevated CK and a family genetic history but without liver damage on computed tomography. He was suspected as having inherited the disorder and was finally diagnosed as having DMD by next-generation sequencing.

Background and Aims: In the REALM (Randomized, Observational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Patients with Chronic HBV Infection) study, 12,378 patients with chronic hepatitis B virus (HBV) infection received up to 10 years of randomized therapy with entecavir or another HBV nucleos(t)ide analogue. Monitored clinical outcome events (COEs) included malignant neoplasms, HBV disease progression events, and deaths. An external event adjudication committee (EAC) was convened to provide real-time review of reported COEs to optimize data quality, and minimize potential adverse effects of the large cohort, interdisciplinary outcome assessments, geographic scope, and long duration. Methods: The EAC comprised an international group of hepatologists and oncologists with expertise in diagnosis of targeted COEs. The EAC reviewed and adjudicated COEs according to prospectively defined diagnostic criteria captured in the EAC charter. Operational processes, including data collection and query procedures, were implemented to optimize efficiency of data recovery to maximize capture of adjudicated COEs, the primary study outcome measure. Results: A total of 1724 COEs were reported and 1465 of these events were adjudicated by the EAC as reported by the investigators (85.0% overall concordance). Concordance by COE type varied: deaths, 99.6%; hepatocellular carcinoma (HCC), 83.3%; non-HCC malignancies, 88.0%; non-HCC HBV disease progression, 68.2%. Reasons for lack of concordance were most commonly lack of adequate supporting data to support an adjudicated diagnosis or evidence that the event pre-dated the study. Conclusions: The REALM EAC performed a critical role in ensuring data quality and consistency; EAC performance was facilitated by well-defined diagnostic criteria, effective data capture, and efficient operational processes.

Trial registration: ClinicalTrials.gov NCT00388674.

Direct-acting antiviral (DAA) therapy is often well-tolerated, and adverse events from DAA therapy are uncommon. We report a case of a woman who underwent orthotopic liver transplant for chronic hepatitis C infection and later developed alloimmune hepatitis shortly after starting DAA therapy for recurrent hepatitis C infection. The patient developed acute alloimmune hepatitis approximately 2 weeks after starting treatment with sofosbuvir, velpatasvir, and voxilaprevir. This case report proposes a dysregulation of immune surveillance due to the DAA stimulation of host immunity and rapid elimination of hepatitis C viral load as a precipitating factor for the alloimmune process, leading to alloimmune hepatitis in a post-transplant patient who starts on DAA.

Globally, hepatitis B virus (HBV) infection and its related liver diseases account for 780,000 deaths every year. Outcomes of HBV infection depend on the interaction between the virus and host immune system. It is becoming increasingly apparent that Kupffer cells (KCs), the largest population of resident and monocyte-derived macrophages in the liver, contribute to HBV infection in various aspects. These cells play an important role not only in the anti-HBV immunity including virus recognition, cytokine production to directly inhibit viral replication and recruitment and activation of other immune cells involved in virus clearance but also in HBV outcome and progression, such as persistent infection and development of end-stage liver diseases. Since liver macrophages play multiple roles in HBV infection, they are directly targeted by HBV to benefit its life cycle. In the present review, we briefly outline the current advances of research of macrophages, especially the studies of their phenotypes, in chronic HBV infection.

Acute liver failure (ALF) is the rapid onset of severe liver dysfunction, defined by the presence of hepatic encephalopathy and impaired synthetic function (international normalized ratio of ≥1.5) in the absence of underlying liver disease. The elevated international normalized ratio value in ALF is often misinterpreted as an increased hemorrhagic tendency, which can lead to inappropriate, prophylactic transfusions of blood products. However, global assessments of coagulopathy via viscoelastic tests or thrombin generation assay suggest a reestablished hemostatic, or even hypercoagulable, status in patients with ALF. Although the current versions of global assays are not perfect, they can provide more nuanced insights into the hemostatic system in ALF than the conventional measures of coagulopathy.

Our previous studies evidenced that quercetin (Q) could be ingested and metabolized by macrophages, and exerted both prophylactic immuno-stimulatory activity and therapeutic anti-inflammatory effects on lipopolysaccharide-treated macrophages ex vivo. To ascertain potential mechanism of anti-inflammatory action by Q, the present study evaluated changes of pro-/anti-inflammatory cytokines and components of inflammation-related intracellular signaling pathways in activated macrophages.

In this ex vivo study, BALB/c mice were first administered intraperitoneally injected with lipopolysaccharide for 12 h; then, mouse peritoneal macrophages were isolated and treated with Q for 3 h in vitro. Quercetin 3-glucuronide (a major metabolite of Q) and dexamethasone (a glucocorticoid) were selected to perform comparative analysis. Relative gene expression amounts of pro-/anti-inflammatory cytokines (TNF-α/IL-10) and components involved in inflammation-related intracellular signaling pathways in macrophages (TLR2, TLR4, NF-κB, JAK2, and STAT3) were measured using two-step reverse transcription and real-time quantitative polymerase chain reaction. STAT3 protein phosphorylation was determined using an in-cell enzyme-linked immunosorbent assay method.

Q decreased TNF-α gene expression amounts and ratios of pro-/anti-inflammatory (TNF-α/IL-10) cytokine gene expressions but increased IL-10 gene expression amounts in activated inflammatory macrophages, supporting a substantial anti-inflammatory potential of Q treatments. Importantly, Q inhibited TLR2 gene expression and phosphorylation of STAT3 protein in the activated inflammatory macrophages.

Our results are the first to suggest that Q inhibits lipopolysaccharide-induced inflammation ex vivo through suppression of TLR2 gene expression and STAT3 protein phosphorylation in activated inflammatory macrophages. Q has potential further application for treating inflammation-associated diseases.

Chronic hepatitis B or C viral infection is a common cause of liver cirrhosis and hepatocellular carcinoma. Fibrosis regression can be achieved after long-term antiviral therapy (AVT). Monitoring of dynamic changes in liver fibrosis after treatment is essential for establishing prognosis and formulation of a follow-up surveillance program. Routine surveillance of fibrosis after AVT by liver biopsy, the gold standard for fibrosis assessment, is hindered by its invasive nature, sampling error and observer variability. Elastography is a noninvasive quantitative alternative that has been widely used and validated for the staging of liver fibrosis prior to treatment. Recently, increasing research interest has been focused on the role of elastography in longitudinal assessment of liver fibrosis after AVT. In this review, the basic principles, acquisition techniques, diagnostic performances, and strengths and limitations of ultrasound elastography and magnetic resonance elastography are presented. Emerging evidence regarding the use of elastography techniques for the monitoring of liver fibrosis after AVT is summarized. Current challenges and future directions are also discussed, designed to optimize the application of these techniques in clinical practice.

Background and Aims: Emitasvir is a new type of hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor, and the data of phase 2 trial has shown emitasvir-sofosbuvir to have good safety and tolerance. We conducted this phase 3 trial to further verify the efficacy and safety.

Methods: We evaluated the antiviral activity and safety of a 12-week regimen of emitasvir phosphate (100 mg) combined with sofosbuvir (400 mg) once daily in non-cirrhotic patients with genotype 1 HCV infection. The primary endpoint was a sustained virological response at 12 weeks (SVR12) after the end of treatment.

Results: Of the 362 patients enrolled in the trial, 39.8% were male, 99.2% had HCV genotype 1b, 0.8% had genotype 1a and 79.8% were treatment-naïve. The average age was 47.2 years. All patients completed the treatment and follow-up. All 3 patients with genotype 1a achieved SVR. Two genotype 1b treatment-naïve patients experienced virologic relapse. The rate of SVR12 was 99.7% (358/359), and SVR24 was 99.4% (357/359) in genotype 1b. Overall, 36.2% had resistance-associated substitutions (RASs) in NS5A and 98.3% had RASs in NS5B at baseline. The RASs at baseline had no effect on the rates of response. Serious adverse events were reported in 16 patients and were not related to emitasvir-sofosbuvir. Most adverse events did not require therapy.

Conclusions: The 12 weeks of treatment with emitasvir-sofosbuvir was a highly efficient and safe treatment for a wide range of patients with HCV genotype 1b infection without cirrhosis, who had not been treated or who had been treated with interferon-based regimen previously.

Background and Aims: Glecaprevir/pibrentasvir is a pangenotypic regimen recently approved for the treatment of chronic hepatitis C virus (HCV) infection. The objective of the present review was to summarize the findings from clinical trials to understand how patient-related factors influence glecaprevir/pibrentasvir efficacy (sustained virologic response rates at 12 weeks’ after treatment [referred to as SVR12]) and safety.

Methods: Data from 21 phase III clinical trials were analyzed.

Results: The integrated efficacy analysis included 4,817 patients. Findings showed 97.5% of all included patients with chronic HCV achieved SVR12 in the intention-to-treat population. SVR12 rate was >95% across subgroups of interest. The integrated safety analysis included 4,015 patients. Findings showed that 64.1% of patients reported an adverse event, and <0.1% of patients reported a serious adverse event related to glecaprevir/pibrentasvir.

Conclusions: These results indicate that the 8- or 12-week glecaprevir/pibrentasvir treatment is effective for patients infected with HCV genotypes 1-6 without or with compensated cirrhosis, with good safety profiles, irrespective of treatment-experience. Glecaprevir/pibrentasvir is a good option for patients with human immunodeficiency virus/HCV coinfection and comorbid HCV and severe renal impairment.

Liver fibrosis is not an independent disease. It refers to the abnormal proliferation of connective tissues in the liver caused by various pathogenic factors. Thus far, liver fibrosis has been considered to be associated with a set of factors, such as viral infection, alcohol abuse, non-alcoholic fatty liver disease, and autoimmune hepatitis, as well as genetic diseases. To date, clinical therapeutics for liver fibrosis still face challenges, as elimination of potential causes and conventional antifibrotic drugs cannot alleviate fibrosis in most patients. Recently, potential therapeutic targets of liver fibrosis, such as metabolism, inflammation, cell death and the extracellular matrix, have been explored through basic and clinical research. Therefore, it is extremely urgent to review the antihepatic fibrosis therapeutics for treatment of liver fibrosis in current clinical trials.

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are slow progressive diseases which have been increasing in prevalence. The pathogeneses of PBC and PSC are incompletely understood but the underlying mechanisms appear to be fundamentally autoimmune in origin. Although PBC and PSC appear to be separate entities, overlap has been described. Diagnosis depends on a combination of serological markers, imaging, and pathological criteria. The mainstay of treatment has been ursodeoxycholic acid and in some cases of extrahepatic biliary obstruction and overlap disorder, endoscopic retrograde cholangiopancreatography has been useful.