Staging Fibrosis in Chronic Viral Hepatitis.

Staging fibrosis accurately has always been a challenge in viral hepatitis and other liver diseases. Liver biopsy is an imperfect gold standard due to its intra and interobserver agreement limitations and additional characteristics such as its safety and cost. Hence, non-invasive tests have been developed to stage liver fibrosis. In addition to serological biomarkers, physical tests with reasonable accuracy are available and adopted in the daily clinic regarding viral hepatitis fibrosis staging. In this review, we discuss the published data regarding the staging of liver fibrosis in chronic hepatitis B and C, emphasizing non-invasive markers of fibrosis, both serological and physical. Moreover, we also discuss a persistent central gap, the evaluation of liver fibrosis after HCV cure.

Combination of FIB-4 with ultrasound surface nodularity or elastography as predictors of histologic advanced liver fibrosis in chronic liver disease.

Reliable and available non-invasive methods for hepatic fibrosis assessment are important in chronic liver disease (CLD). Our aim was to compare stepwise algorithms combining standard ultrasound with serum markers and transient elastography (TE) for detecting advanced fibrosis (F3-4) and cirrhosis. Retrospective single center study between 2012 and 2018 of CLD patients with biopsy, TE, blood tests, and liver ultrasound parameters of surface nodularity (SN), lobar redistribution, and hepatic vein nodularity. Our cohort included 157 patients (51.6% males), mean age 47.6 years, predominantly non-alcoholic fatty liver disease and viral hepatitis (61%), with F3-4 prevalence of 60.5%. Area under the curve for F3-4 was 0.89 for TE ≥ 9.6 kPa and 0.80 for FIB-4 > 3.25. In multivariate modeling, TE ≥ 9.6 kPa (OR 21.78) and SN (OR 3.81) had independent association with F3-4; SN (OR 5.89) and TE ≥ 10.2 kPa (OR 15.73) were independently associated with cirrhosis. Two stepwise approaches included FIB-4 followed by SN or TE; sensitivity and specificity of stepwise SN were 0.65 and 1.00, and 0.89 and 0.33 for TE ≥ 9.6 kPa, respectively. Ultrasound SN and TE were independently predictive of F3-4 and cirrhosis in our cohort. FIB-4 followed by SN had high specificity for F3-4.

Viral hepatitis associated hepatocellular carcinoma on the African continent, the past, present, and future: a systematic review.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in Africa. In Africa, the major causes of HCC include chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). Knowledge of the changes in the incidence of viral hepatitis-associated HCC over time and the factors responsible for such changes is key in informing policies for the prevention of viral hepatitis-associated HCC in Africa. AIM: The study aimed to systematically summarize the changes in the prevalence of viral hepatitis among HCC patients and the overall effect of the prevalence of viral hepatitis on the incidence of HCC over the past four decades in Africa (1980-2019). METHODS: A literature search was conducted in MEDLINE (PubMed), Google Scholar, Science Direct, Scopus, Web of Science, and African wide web for articles published on viral hepatitis-associated HCC in Africa from 1980 to 2019. The abstracts of the articles were screened for eligibility and those meeting the inclusion criteria were retrieved and reviewed. RESULTS: A total of 272 studies were included in the analysis. Viral hepatitis-related HCC incidence changed by 1.17% (95% confidence interval (CI): 0.63-1.71, p < 0.001), 0.82% (95% CI: 0.45-1.18, p < 0.001), and 3.34% (95% CI: 2.44-4.25, p < 0.001) for every 1% change in the prevalence of HBV, HCV, and hepatitis D virus (HDV) respectively, per decade. The incidence of HBV-related HCC decreased by - 0.50% (95% CI: - 0.74 - - 0.25, p < 0.001) over the last 40 years, while HCV-related HCC increased. CONCLUSION: Overall, the incidence of viral hepatitis-associated HCC has not declined, mainly due to no decline in the prevalence of HCV, HDV, and the high number of chronic hepatitis B carriers on the African continent. There is an urgent need for the allocation of resources for the implementation of treatment and preventive programs for HBV, HCV, HDV, and HCC in Africa. This systematic review is registered with PROSPERO®, number CRD42020169723.

Role of extracellular vesicles in liver diseases and their therapeutic potential.

More than eight hundred million people worldwide have chronic liver disease, with two million deaths per year. Recurring liver injury results in fibrogenesis, progressing towards cirrhosis, for which there doesn't exists any cure except liver transplantation. Better understanding of the mechanisms leading to cirrhosis and its complications is needed to develop effective therapies. Extracellular vesicles (EVs) are released by cells and are important for cell-to-cell communication. EVs have been reported to be involved in homeostasis maintenance, as well as in liver diseases. In this review, we present current knowledge on the role of EVs in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, alcohol-associated liver disease, chronic viral hepatitis, primary liver cancers, acute liver injury and liver regeneration. Moreover, therapeutic strategies involving EVs as targets or as tools to treat liver diseases are summarized.

Pathogenesis of Viral Hepatitis-Induced Chronic Liver Disease: Role of Extracellular Vesicles.

Extracellular vesicles are encapsulated lipid nanoparticles secreted by a variety of cell types in living organisms. They are known to carry proteins, metabolites, nucleic acids, and lipids as their cargoes and are important mediators of intercellular communication. The role of extracellular vesicles in chronic liver disease has been reported. Chronic liver disease such as viral hepatitis accounts for a significant mortality and morbidity burden worldwide. Hepatic fibrosis has been commonly associated with the chronic form of viral hepatitis, which results in end-stage liver disease, including cirrhosis, liver failure, and carcinoma in some patients. In this review, we discuss the potential role of extracellular vesicles in mediating communication between infectious agents (hepatitis B and C viruses) and host cells, and how these complex cell-cell interactions may facilitate the development of chronic liver disease. We will further discuss how understanding their biological mechanism of action might be beneficial for developing therapeutic strategies to treat chronic liver disease.

Clinical application of ultrasonography-guided percutaneous liver biopsy and its safety over 18 years.

BACKGROUND/AIMS: Liver biopsy (LB) remains the gold standard for the evaluation of liver disease. However, over the past two decades, many noninvasive tests have been developed and utilized in clinical practice as alternatives to LB. The aim of this study was to evaluate the clinical use and safety of LB in the era of noninvasive assessment of liver fibrosis. METHODS: This retrospective study included 1,944 consecutive cases of LB performed between 2001 and 2018 in a tertiary hospital. All of the LBs were conducted under ultrasonography guidance with 18-gauge cutting needles. RESULTS: LBs were performed an average of approximately 108 times per year during the study period. Chronic hepatitis B (25.3%) and suspected malignancy (20.5%) were the two most common indications for LB. The use of LB for nonalcoholic fatty liver disease increased from 8.1% to 17.2% in the past 5 years compared to the last 10 years, while that for viral hepatitis decreased from 40.3% to 18.9%. Discordance rate between the suspected diagnosis and the final diagnosis was 2.6% (51 cases). The overall rate of major adverse events was 0.05% (one case), which involved delayed bleeding at the biopsy site. Liver cirrhosis was observed in 563 cases (28.9%), and the presence of cirrhosis did not affect the frequency of complications (P=0.289). CONCLUSION: LB is widely used in clinical practice as an irreplaceable diagnostic tool, even in the era of noninvasiveness. Ultrasonography-guided LB can be performed safely in patients with liver cirrhosis.

Liquid Biopsy for the Diagnosis of Viral Hepatitis, Fatty Liver Steatosis, and Alcoholic Liver Diseases.

During the progression from hepatitis to fibrosis, cirrhosis, and liver failure, the accumulation of stressed/damaged hepatocyte elements associated with liver inflammation is critical. The causes of hepatocyte injuries include viral hepatitis infections, alcoholic hepatitis, and non-alcoholic fatty liver disease. Hepatocyte-derived extracellular vesicles (Hep-EVs) released from stressed/damaged hepatocytes are partly responsible for liver disease progression and liver damage because they activate non-parenchymal cells and infiltrate inflammatory cells within the liver, which are in turn are an important source of EVs. This cell-to-cell signaling is prevalent during inflammation in many liver diseases. Accordingly, special emphasis should be placed on liquid biopsy methods for the long-term monitoring of chronic liver diseases. In the present review, we have highlighted various aspects of current liquid biopsy research into chronic liver diseases. We have also reviewed recent progress on liquid biopsies that focus on cell-free DNA (cfDNA), long non-coding RNA (lncRNA), and the proteins in EVs as potential diagnostic tools and novel therapeutic targets in patients with viral hepatitis, fatty liver steatosis, and alcoholic liver diseases.

Liver, Tumor and Viral Hepatitis: Key Players in the Complex Balance Between Tolerance and Immune Activation.

Liver cancer is the third most common cause of cancer related death in the World. From an epidemiological point of view the risk factors associated to primary liver cancer are mainly viral hepatitis infection and alcohol consumption. Even though there is a clear correlation between liver inflammation, cirrhosis and cancer, other emerging liver diseases (like fatty liver) could also lead to liver cancer. Moreover, the liver is the major site of metastasis from colon, breast, ovarian and other cancers. In this review we will address the peculiar status of the liver as organ that has to balance between tolerance and immune activation. We will focus on macrophages and other key cellular components of the liver microenvironment that play a central role during tumor progression. We will also discuss how current and future therapies may affect the balance toward immune activation.

Novel reliability criteria for controlled attenuation parameter assessments for non-invasive evaluation of hepatic steatosis.

BACKGROUND: There is conflicting evidence regarding reliability criteria for the controlled attenuation parameter (CAP; a marker for hepatic steatosis [HS]). Thus, we assessed the diagnostic performance of CAP according to different reliability criteria based on real-world data from an academic centre. METHODS: Patients undergoing measurement of CAP and liver biopsy (±6 months) at the Medical University of Vienna were included. HS was assessed according to SAF score. RESULTS: In total 319 patients were included. The main aetiologies were non-alcoholic fatty liver disease (NAFLD, n = 177, 55.5%), viral hepatitis (n = 49, 15.4%), and alcoholic liver disease (ALD, n = 29, 9.1%). Histological steatosis and fibrosis stages were: S0: 93 (29.2%), S1: 100 (31.3%), S2: 67 (21.0%), and S3: 59 (18.5%); F0/F1: 150 (47.0%), F2: 47 (14.7%), and F3/F4: 122 (48.3%). In the overall cohort, the area under the receiver operating characteristic curve (AUC) of CAP was 0.843 (95% confidence interval [CI]: 0.798-0.887) for diagnosing HS ≥ S1), 0.789 (95%CI: 0.740-0.839) for ≥S2, and 0.767 (95%CI: 0.712-0.823) for S3. CAP corrections as suggested by Karlas et al. did not improve the diagnostic performance. Importantly, the AUC of CAP for HS ≥ S1 was numerically highest in patients with CAP-IQR/median<0.10 or <0.20 (obtained in 37.9% and 74.9%), in whom CAP also had better diagnostic performance, as compared with patients not meeting these criteria. Moreover, it was substantially higher in 288 (90.3%) patients with CAP-IQR/median<0.3: 0.856 (95%CI: 0.809-0.903) vs. patients not meeting this criterion (0.530 [95%CI: 0.309-0.751]). In contrast, the previously suggested reliability criterion of CAP-IQR<40 dB/m was not associated with an improved diagnostic performance for HS≥S1 (0.866 [95%CI: 0.812-0.920] vs. 0.799 [95%CI: 0.717-0.881]) and was only obtained in 199 (62.4%) patients. CONCLUSION: CAP-IQR/median<0.1, <0.2, and <0.3 identify reliable measurements for diagnosing any hepatic steatosis (≥S1). Importantly, CAP-IQR/median<0.3 has a considerably higher applicability in clinical practice, as compared with the previously suggested CAP-IQR<40 dB/m criterion.

Major Complications of Pediatric Percutaneous Liver Biopsy Do Not Differ Among Physicians With Different Degrees of Training.

INTRODUCTION: The objective was to compare safety of pediatric percutaneous liver biopsy (PLB) performed by fellows or staff physicians. METHODS: Outcomes of 212 PLB completed by first-year pediatric gastroenterology fellows or by staff physicians over 8 years were analyzed and compared. RESULTS: Approximately 81.5% of the biopsies were completed by trainees. No significant differences were found between groups (fellows vs staff) regarding number of punctures (median of 1.7 for both), nonrepresentative biopsies (4.2% vs 2.6%), and hemoglobin drop (median of 0.7 vs 0.5 g/L). DISCUSSION: Complications of pediatric PLB are uncommon and did not differ among physicians with different training levels.

Poor Concordance Between Liver Stiffness and Noninvasive Fibrosis Scores in HIV Infection Without Viral Hepatitis.

People living with human immunodeficiency virus (PLWH) are at higher risk of liver fibrosis compared with the general population. As liver fibrosis is independently associated with poor long-term liver related outcomes and mortality,1 early detection is extremely important. Liver biopsy is considered gold standard for the diagnosis of liver fibrosis. However, this invasive procedure is only suitable for a selected group of patients because of the risk of serious complications. We aimed to estimate the concordance between vibration-controlled transient elastography (VCTE) and simple noninvasive liver fibrosis scores-Fibrosis-4 index (FIB4), aspartate aminotransferase-to-platelet ratio index (APRI), and nonalcoholic fatty liver disease fibrosis score (NFS)-in PLWH without viral hepatitis.

ECM1 Prevents Activation of Transforming Growth Factor ß, Hepatic Stellate Cells, and Fibrogenesis in Mice.

BACKGROUND & AIMS: Activation of TGFB (transforming growth factor ß) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS: We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Δhep). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Δhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

A five lncRNA signature for prognosis prediction in hepatocellular carcinoma.

This study was conducted to screen prognosis­â€‹associated long­noncoding RNAs (lncRNAs) and a prognosis assessment model in hepatocellular carcinoma (HCC). lncRNA­ and mRNA­sequencing data of early­stage HCC samples were downloaded from The Cancer Genome Atlas database. The samples were divided into training set and validation set. Differentially expressed lncRNAs (DELs) between poor prognosis and good prognosis samples were screened with DEseq and edgeR. Cox regression analysis was conducted to identify prognosis­associated lncRNAs in the training set. A prognosis risk assessment model was established to calculate the risk score for each patient in the training set, and the prognosis prediction function was tested and validated in the validation dataset. The connection between the risk assessment model and clinical features was analyzed. A co­expression network between lncRNAs and corresponding genes was constructed, and functional enrichment was performed for these genes. A total of 81 DELs were screened between poor and good prognosis samples in the training set, and 43 prognosis­associated lncRNAs were observed. Of these DELs, five were used to construct the risk assessment model (RP11­325L7.2, DKFZP434L187, RP11­100L22.4, DLX2­AS1 and RP11­104L21.3). Low­risk samples exhibited longer survival time compared with the high­risk samples. The five lncRNAs exhibited significant differences in expression levels between different prognosis groups. Risk score was an independent prognostic factor for HCC. In the entire set, the low­risk group demonstrated significantly better prognosis compared with the high­risk group, even across all age, sex and alcohol consumption subgroups. 'Nucleoside­triphosphatase regulator activity', 'GTPase regulator activity', 'enzyme binding', 'peroxisome proliferator­activated receptor signaling pathway' and 'fatty acid metabolism' were the most significantly enriched functional terms. The signature lncRNAs screened in this study may have constitute novel strategies and biomarkers that predict the prognosis of HCC, and these may also contribute to a deeper understanding of the mechanisms underlying HCC development.

Ectonucleotidases in Intestinal and Hepatic Inflammation.

Purinergic signaling modulates systemic and local inflammatory responses. Extracellular nucleotides, including eATP, promote inflammation, at least in part via the inflammasome upon engagement of P2 purinergic receptors. In contrast, adenosine generated during eATP phosphohydrolysis by ectonucleotidases, triggers immunosuppressive/anti-inflammatory pathways. Mounting evidence supports the role of ectonucleotidases, especially ENTPD1/CD39 and CD73, in the control of several inflammatory conditions, ranging from infectious disease, organ fibrosis to oncogenesis. Our experimental data generated over the years have indicated both CD39 and CD73 serve as pivotal regulators of intestinal and hepatic inflammation. In this context, immune cell responses are regulated by the balance between eATP and adenosine, potentially impacting disease outcomes as in gastrointestinal infection, inflammatory bowel disease, ischemia reperfusion injury of the bowel and liver, autoimmune or viral hepatitis and other inflammatory conditions, such as cancer. In this review, we report the most recent discoveries on the role of ENTPD1/CD39, CD73, and other ectonucleotidases in the regulation of intestinal and hepatic inflammation. We discuss the present knowledge, highlight the most intriguing and promising experimental data and comment on important aspects that still need to be addressed to develop purinergic-based therapies for these important illnesses.

Role of Autophagy in Chronic Liver Inflammation and Fibrosis.

Autophagy entails the removal of dysfunctional components to maintain cellular homeostasis. Over the years, studies of autophagy demonstrated its complex physiological and pathological roles in the liver. Apart from regulation of normal metabolic functions such as glycogenolysis, glycogenesis, and ß-oxidation, autophagy also contributes to the modulation of various liver diseases. In this review, we provide a concise overview of the role of autophagy in regulating hepatic metabolism in healthy conditions and various chronic liver diseases. A well-rounded understanding of the role of autophagy may provide insight for future medical advancements in the field of hepatology.

Donor derived HSV hepatitis in a kidney transplant recipient leading to liver fibrosis and portal hypertension.

The unexpected transmission of donor-derived infection through organ transplantation is a rare event with current donor screening practices. In this case report we describe a probable donor-derived transmission of Herpes Simplex Virus (HSV)-2 via deceased donor kidney transplantation resulting in HSV hepatitis in the recipient. This manifested as acute liver failure which resolved with appropriate anti-viral therapy. Following recovery from the acute liver insult, the patient developed fibrotic liver morphology and portal hypertension, an unusual departure from the typical course.

Epidemiology and Management of Hepatocellular Carcinoma.

The major risk factors for hepatocellular carcinoma (HCC) in contemporary clinical practice are becoming increasingly related to sustained virological response after hepatitis C, suppressed hepatitis B virus during treatment, and alcoholic and nonalcoholic fatty liver disease. We review the emerging data on the risk and determinants of HCC in these conditions and the implications of HCC surveillance. However, from a public health perspective, active hepatitis C and B continue to drive most of the global burden of HCC. In United States, the age-adjusted incidence rates of HCC in Hispanics have surpassed those of HCC in Asians. Prognosis in HCC is complex because of the competing risk imposed by underlying cirrhosis and presence of malignancy. In addition to tumor burden, liver function and performance status; additional parameters including tumor biopsy, serum markers, and subclassification of current staging systems; and taking into account patterns of tumor progression may improve patient selection for therapy. Advancements in the treatment of HCC have included identification of patients who are most likely to derive a clinically significant benefit from the available therapeutic options. Additionally, the combination strategies of locoregional therapies and/or systemic therapy are being investigated.

NK cells in liver homeostasis and viral hepatitis.

As an important member of the innate immune system, natural killer (NK) cells are well known for their rapid and efficient immune responses against infectious agents and tumors. NK cells are widely distributed throughout the body and are particularly enriched within the liver, where they display unique phenotypic and functional properties, playing important roles in various liver diseases. Herein, we present an overview of liver NK cell properties with regard to phenotype, function, and subset composition at steady state, and we also summarize the complex reciprocal interactions between liver NK cells and other cell types within the local environment of the liver. We also provide an overview of recent advances demonstrating the roles of NK cells in viral hepatitis, including a discussion of NK cell altered states and their beneficial versus harmful effects during hepatitis B virus and hepatitis C virus infection.