Metabolic (dysfunction)-associated fatty liver disease (MAFLD) affects a third of the population and is a leading cause of liver-related death. Since no effective treatments exist, novel approaches to drug development are required. Unfortunately, outdated terminology and definitions of the disease are hampering efforts to develop new drugs and treatments. An international consensus panel has put forth an influential proposal for the disease to be renamed from nonalcoholic fatty liver disease (NAFLD) to MAFLD, including a proposal for how the disease should be diagnosed. As allies with the many stakeholders in MAFLD care―including patients, patients’ advocates, clinicians, researchers, nurse and allied health groups, regional societies, and others―we are aware of the negative consequences of the NAFLD term and definition. We share the sense of urgency for change and will act in new ways to achieve our goals. Although there is much work to be done to overcome clinical inertia and reverse worrisome recent trends, the MAFLD initiative provides a firm foundation to build on. It provides a roadmap for moving forward toward more efficient care and affordable, sustainable drug and device innovation in MAFLD care. We hope it will bring promising new opportunities for a brighter future for MAFLD care and improve care and outcomes for patients of one of the globe’s largest and costliest public health burdens. From this viewpoint, we have revisited this initiative through the perspectives of drug development and regulatory science.

Defects in mitochondria are responsible for various genetic and acquired diseases. Mitochondrial transplantation, a method that involves introduction of healthy donor mitochondria into cells with dysfunctional mitochondria, could offer a novel approach to treat such diseases. Some studies have demonstrated the therapeutic benefit of mitochondrial transplantation and targeted delivery in vivo and in vitro within hepatocytes and the liver. This review discusses the issues regarding isolation and delivery of mitochondria to hepatocytes and the liver, and examines the existing literature in order to elucidate the utility and practicality of mitochondrial transplantation in the treatment of liver disease. Studies reviewed demonstrate that mitochondrial uptake could specifically target hepatocytes, address the challenge of non-specific localization of donor mitochondria, and provide evidence of changes in liver function following injection of mitochondria into mouse and rat disease models. While potential benefits and advantages of mitochondrial transplantation are evident, more research is needed to determine the practicality of mitochondrial transplantation for the treatment of genetic and acquired liver diseases.

Nonalcoholic fatty liver disease (NAFLD) is a multisystemic clinical condition that presents with a wide spectrum of extrahepatic manifestations, such as obesity, type 2 diabetes mellitus, metabolic syndrome, cardiovascular diseases, chronic kidney disease, extrahepatic malignancies, cognitive disorders, and polycystic ovarian syndrome. Among NAFLD patients, the most common mortality etiology is cardiovascular disorders, followed by extrahepatic malignancies, diabetes mellitus, and liver-related complications. Furthermore, the severity of extrahepatic diseases is parallel to the severity of NAFLD. In clinical practice, awareness of the associations of concomitant diseases is of major importance for initiating prompt and timely screening and multidisciplinary management of the disease spectrum. In 2020, a consensus from 22 countries redefined the disease as metabolic (dysfunction)-associated fatty liver disease (MAFLD), which resulted in the redefinition of the corresponding population. Although the patients diagnosed with MAFLD and NAFLD mostly overlap, the MAFLD and NAFLD populations are not identical. In this review, we compared the associations of key extrahepatic diseases between NAFLD and MAFLD.

Hepatocellular carcinoma (HCC), one of the most common malignant tumors worldwide, is known for its grim prognosis, with untreated life expectancy being only a matter of months after the diagnosis. The difficulty in making a diagnosis early is one of the main contributing factors to the poor prognosis. Alpha-fetoprotein (AFP) had long been used as a surveillance tool, but suboptimal specificity and sensitivity has prompted liver societies to abandon the recommendation for its universal use, even in combination with ultrasonography. Most studies have shown no obvious correlation between serum AFP level and HCC tumor size, stage, or survival post-diagnosis. However, some studies concluded that a gradual rise or persistent elevation in AFP were positive predictors for tumor development. Other studies reported a fall in AFP followed by a rise in patients with HCC as well as persistently rising AFP levels without development of HCC on follow up. Our calculation of the sensitivity and specificity of persistently rising AFP for HCC were both low, at 60% and 35.8%, respectively, indicating that the presence of persistently rising AFP per se did not offer diagnostic benefit. In addition, our calculated mean slopes of persistently rising AFP levels in HCC and non-HCC patients were numerically very different, but the difference was not statistically significant. We conclude that the published data do not support a role for rising AFP levels per se in the diagnosis of HCC.

It is challenging to predict the 90-day outcomes of patients infected with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) via prevailing predictive models. This study aimed to develop an innovative model to enhance the analytical efficacy of 90-day mortality in HBV-ACLF.

In this study, 149 HBV-ACLF patients were evaluated by constructing a death risk prediction nomogram. Bootstrap resampling and an independent validation cohort comprising 31 patients from June 2019 to February 2020 were assessed for model confirmation.

The nomogram was constructed by entering and identifying five factors (age, total bilirubin, prothrombin activity (PTA), lymphocyte (L)%, and monocyte (M)%. Healthy refinement was achieved from the nomogram analysis, where the area under the receiver operating characteristic curve was 0.864 for the training cohort and 0.874 was achieved for the validation cohort. There was admirable concordance between the predicted and true results in the equilibrium curve. The decision curve assessment revealed the useful clinical application of the nomogram.

We constructed an innovative nomogram and validated it for the prediction of 90-day HBV-ACLF patient outcomes. This model might help develop optimized treatment protocol recommendations for HBV-ACLF patients.

Severe acute respiratory syndrome coronavirus (SARS-CoV) 2 infection has caused millions of deaths worldwide, pushing the urgent need for an efficient treatment. Nonstructural protein 15 (NSP15) is a promising target due to its importance for SARS-CoV-2’s evasion of the host’s innate immune response.

Using the crystal structure of SARS-CoV-2 NSP15 endoribonuclease, we developed a pharmacophore model of the functional centers in the NSP15 inhibitor’s binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. The conformations of these compounds underwent three-dimensional fingerprint similarity clustering, and possible conformers were docked to the NSP15 binding pocket. We also simulated the docking of random compounds to the NSP15 binding pocket for comparison.

This search identified 170 compounds as potential inhibitors of SARS-CoV-2 NSP15. The mean free energy of docking for the group of potential inhibitors was significantly less than that for the group of random compounds. Twenty-one of the compounds identified as potential NSP15 inhibitors were antiviral compounds that inhibited a range of viruses, including Middle East respiratory syndrome, SARS-CoV, and even SARS-CoV-2. Eight of the selected antiviral compounds in cluster A are pyrimidine analogues, six of which are currently used in a clinical setting. Four tyrosine kinase inhibitors were identified with potential SARS-CoV-2 inhibition, which is consistent with previous studies showing some kinase inhibitors acting as antiviral drugs.

We recommend that the 21 selected antiviral compounds are tested as COVID-19 therapeutics.

The prevalence of metabolic (dysfunction)-associated fatty liver disease (MAFLD) is rapidly increasing and affects up to two billion individuals globally, and this has also resulted in increased risks for cirrhosis, hepatocellular carcinoma, and liver transplants. In addition, it has also been linked to extrahepatic consequences, such as cardiovascular disease, diabetes, and various types of cancers. However, only a small proportion of patients with MAFLD develop these complications. Therefore, the identification of high-risk patients is paramount. Liver fibrosis is the major determinant in developing these complications. Although, liver biopsy is still considered the gold standard for the assessment of patients with MAFLD. Because of its invasive nature, among many other limitations, the search for noninvasive biomarkers for MAFLD remains an area of intensive research. In this review, we provide an update on the current and future biomarkers of MAFLD, including a discussion of the associated genetics, epigenetics, microbiota, and metabolomics. We also touch on the next wave of multiomic-based biomarkers.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in Wuhan, China, in late 2019. Responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, SARS-CoV-2 is one of three structurally similar beta-coronaviruses that can cause a strong upregulation of cytokines referred to as cytokine release syndrome (CRS). Unresolved CRS leads to respiratory symptoms, including pneumonia, and in more severe cases, acute respiratory distress syndrome (ARDS). Although COVID-19 is widely known for these hallmark respiratory symptoms, it also impacts the gut, causing gastrointestinal (GI) tract inflammation and diarrhea. COVID-19’s GI symptoms may be due to the high intestinal expression of angiotensin converting enzyme-2 receptors, which are for the binding of SARS-CoV-2 viral particles. Reports have shown that SARS-CoV-2 can be passed through fecal matter, with one study finding that 48.1% of COVID-19 patients expressed viral SARS-CoV-2 mRNA in their stool. Given that the GI tract is a target tissue affected by COVID-19, this causes concern for those with underlying GI pathologies, such as inflammatory bowel disease (IBD). Regrettably, there have been only limited studies on the impact of COVID-19 on gut health, and the impact of COVID-19 on intestinal inflammation among IBD patients remains unclear. In particular, questions regarding susceptibility to SARS-CoV-2 infection, clinical impact of COVID-19 on IBD, and the potential influence of age, sex, and immunosuppressant medications are still poorly understood. An improved understanding of these issues is needed to address the unique risks of COVID-19 among IBD patients, as well as the potential impact of SARS-CoV-2 on the host intestinal microbiota.

The anticipated fear of serious outcomes in coronavirus infected liver transplant recipients led to disruption of transplant services globally. The aim of our study was to analyze COVID-19 severity in transplant recipients and to compare the difference of COVID-19 clinical outcomes in early (<1 year) vs. late (>1 year) post-transplant period.

41 post-living donor liver transplant recipients with COVID-19 infection were studied retrospectively from 1st April 2020 to 28th February 2021.

The median age was 49.00 years with a male preponderance (80.49%). Fifteen patients had infection within 1 year of transplant and 26 were infected after 1 year of transplant. The overall median interval between transplantation and COVID-19 diagnosis was 816.00 days. Fever and malaise were the common presenting symptoms. The most common associated comorbidities were diabetes mellitus (65.85%) and hypertension (46.34%). The severity of illness was mild in 28 (68.29%), moderate in 4 (9.76%), severe in 6 (14.63%) and critical in 3 (7.32%). To identify associated risk factors, we divided our patients into less severe and more severe groups. Except for lymphopenia, there was no worsening of total bilirubin, transaminases, alkaline phosphatase, and gamma-glutamyl transferase in the more severe group. Eight (19.51%) patients required intensive care unit admission and three (7.32%) died, while none suffered graft rejection. In recipients with early vs. late post-transplant COVID-19 infection, there were similar outcomes in terms of severity of COVID-19 illness, intensive care unit care need, requirement of respiratory support, and death.

Living donor liver transplantation can be performed during the COVID-19 pandemic without the fear of poor recipient outcome in cases of unfortunate contraction of severe acute respiratory syndrome coronavirus-2.

Pathology translational research pipelines are complex, as many studies rely on analyses of tissue immunohistochemistry. High-throughput methodologies such as tissue microarrays (TMAs) have been critical for many recent advancements as large datasets are necessary to make detailed disease and biologic discoveries. Currently, TMA molds can be purchased from online vendors or constructed in house with complex machinery. However, there are certain limitations to these molds, such as cost per mold and inability for selection of core slot patterns. Thus, we propose a practical and cost-effective method for constructing a silicone-based rubber TMA mold that can be used to create a paraffin template block. Our results show that these self-manufactured molds are durable, effective and easy to customize, reducing operating costs and creating flexibility for users. Furthermore, in leveraging this technique, we describe coupling TMA-prepared slides with a rapid research-focused digital analytic pipeline that allows for a streamlined method of quantitative and qualitative companion discovery.

Cartilage destruction is central in the pathogenesis of osteoarthritis (OA), an age-related chronic degenerative disease. Cartilage degeneration has been postulated to occur due to chondrocyte senescence. On the other hand, type 2 diabetes mellitus (T2DM) is an independent risk factor for OA initiation and progression, bringing about the concept of “diabetic OA (DM-OA).” Aberrant metabolic pathways in T2DM promote a chronic inflammatory environment that favors cell apoptosis and senescence. However, it is still unclear if the cartilage of diabetic OA patients contains a higher amount of senescent chondrocytes compared to nondiabetic patients.

We established mouse models of OA and DM-OA and determined the integrity of cartilage with and without OA induction with Safranin-O/Fast Green staining. MicroRNA-24a (miR-34a) and sirtuin 1 (SIRT1) cartilage expression was quantified using reverse transcription polymerase chain reaction. Chondrocytes were transfected with either miR-34a mimic or anti-miR-34a, and subsequent expression of SIRT1 and aging-related proteins was determined by western blotting and reverse transcription polymerase chain reaction and followed by quantification of senescent cells using a senescence-associated beta-galactosidase staining kit.

This study showed that miR-34a expression was elevated in the cartilage of diabetic OA models. miR-34a may be critical for chondrocyte senescence, likely through its action on SIRT1 expression. This hypothesis was supported by reduced SIRT1 expression in the cartilage of diabetic OA models.

Our findings suggest that miR-34a/SIRT1 plays a critical role in the development and progression of diabetic OA. Targeting miR-34a/SIRT1 may function as a novel pathway for OA prevention through the elimination of senescent chondrocytes.

A new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in 2020. The change from nonalcoholic fatty liver disease (NAFLD) to MAFLD highlights the metabolic abnormalities that accompany fatty liver. The diagnosis of MAFLD does not require exclusion of secondary causes of liver diseases and alcohol consumption. Thus, MAFLD may coexist with other types of liver diseases, such as viral hepatitis, a disease that remains the most common cause of liver disease-related death. With the increasing prevalence of MAFLD, patients with coincidental MAFLD and viral hepatitis are frequently encountered in clinical practice. In this review, we mainly summarize the mutual relationship between hepatitis B/C and systematic metabolism dysfunction related to MAFLD. We discuss the impact of MAFLD on progression of viral hepatitis and the therapies. Some unaddressed clinical problems related to concomitant MAFLD and viral hepatitis are also identified.

This paper gives the full analytical solution of the generic set of ordinary differential equations that define one-compartment toxicokinetic models. These models describe the uptake and elimination processes that occur within living organisms when exposed to chemical substances. The models solved in this paper consider living organisms as a unique compartment, into which a parent compound enters via several possible exposure routes and from which it is eliminated as well as its potential metabolites. Benefiting from generic solutions of one-compartment toxicokinetic models is particularly useful when fitting them to experimental data, facilitating the writing of the inference algorithms leading to parameter estimates. Additionally, these models are of crucial interest in environmental risk assessment for the calculation of bioaccumulation metrics as required by regulators in support of decision-making when they evaluate dossiers for marketing authorisation of active substances.

This study aimed to determine the performance of the non-invasive score using noncontrast-enhanced MRI (CHESS-DIS score) for detecting portal hypertension in cirrhosis.

In this international multicenter, diagnostic study (ClinicalTrials.gov, NCT03766880), patients with cirrhosis who had hepatic venous pressure gradient (HVPG) measurement and noncontrast-enhanced MRI were prospectively recruited from four university hospitals in China (n=4) and Turkey (n=1) between December 2018 and April 2019. A cohort of patients was retrospectively recruited from a university hospital in Italy between March 2015 and November 2017. After segmentation of the liver on fat-suppressed T1-weighted MRI maps, CHESS-DIS score was calculated automatically by an in-house developed code based on the quantification of liver surface nodularity.

A total of 149 patients were included, of which 124 were from four Chinese hospitals (training cohort) and 25 were from two international hospitals (validation cohort). A positive correlation between CHESS-DIS score and HVPG was found with the correlation coefficients of 0.36 (p<0.0001) and 0.55 (p<0.01) for the training and validation cohorts, respectively. The area under the receiver operating characteristic curve of CHESS-DIS score in detection of clinically significant portal hypertension (CSPH) was 0.81 and 0.9 in the training and validation cohorts, respectively. The intraclass correlation coefficients for assessing the inter- and intra-observer agreement were 0.846 and 0.841, respectively.

A non-invasive score using noncontrast-enhanced MRI was developed and proved to be significantly correlated with invasive HVPG. Besides, this score could be used to detect CSPH in patients with cirrhosis.

To achieve the goal of the World Health Organization to eliminate viral hepatitis as a major public health threat by 2030, the Chinese Society of Infectious Diseases and the Chinese Society of Hepatology convened an expert panel in 2019 to update the guidelines for the prevention and treatment of chronic hepatitis B (CHB). The current guidelines cover recent advances in basic, clinical, and preventive studies of CHB infection and consider the actual situation in China. These guidelines are intended to provide support for the prevention, diagnosis, and treatment of CHB.

Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is a subtype of uncommon aggressive large B-cell lymphomas primarily occurring in mediastinum although rare cases with non-thymic type of PMBL have been reported. Typical PMBL has characteristic clinical, morphological, and immunophenotypic features which the pathologists use as diagnostic paradigm in routine practice. However, the diagnosis can be occasionally challenging due to the overlapping clinicopathologic features with other lymphomas, among which are nodular sclerosis classic Hodgkin lymphoma, systemic diffuse large B-cell lymphoma (DLBCL) involving mediastinum, and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma (gray zone lymphoma). Recent depictions of the characteristic genetic/ molecular aberrations and unique gene expression profiling in PMBL have provided a robust tool to significantly improve the diagnostic accuracy. In addition, the progresses in understanding the pathogenesis of PMBL have paved the way discovering novel therapeutic agents for patients with refractory/relapsed disease.

Nonalcoholic fatty liver disease (NAFLD) is reported to affect 20-30% of adults and is accompanied by various metabolic comorbidities, where the economic and clinical burden of NAFLD is attributed to the progression of liver disease as well as the presence of extrahepatic diseases. Chronic kidney disease (CKD), which has a high incidence rate, high morbidity and mortality rates, and high medical costs, has been linked to NAFLD. CKD is associated with some metabolism-related risk factors that overlap with metabolic comorbidities of NAFLD. Therefore, to investigate the potential factors that influence CKD occurrence, the association between NAFLD and CKD should be clarified. Some studies have confirmed that NAFLD influences the occurrence and severity of CKD, whereas some studies have indicated that there is no correlation. In this review, the results of a few studies have been discussed, the potential risk factors for CKD in NAFLD are explored, and the respective biological mechanisms are elaborated to help clinicians identify CKD in patients much earlier than it is diagnosed now and thus help in reducing the incidence of liver and kidney transplants.

Histoplasma capsulatum is the most common cause of endemic mycosis in developing countries. It is a self-limited and asymptomatic disease in immunocompetent individuals but remains a frequent cause of opportunistic infection in patients with compromised immune status. Liver involvement as a part of disseminated histoplasmosis is well known. However, liver infection as a primary manifestation of histoplasmosis without evidence of primary lung involvement is rare. In conclusion, clinicians should be aware of isolated histoplasmosis affecting the hepatobiliary system, and careful evaluation is warranted to confirm the diagnosis. Given the appropriate clinical context, histoplasmosis should be considered in both immunocompetent and immunocompromised patients, regardless of pulmonary symptoms, in non endemic as well as endemic areas.

The novel coronavirus disease 2019 (COVID-19) pandemic has impacted health care worldwide, with specific patient populations, such as those with diabetes, cardiovascular disease, and chronic lung disease, at higher risk of infection and others at higher risk of disease progression. Patients with decompensated cirrhosis fall into the latter category and are a unique group that require specific treatment and management decisions because they can develop acute-on-chronic liver failure. In liver transplant recipients, the atypical immunity profile due to immunosuppression protects against downstream inflammatory responses triggered by COVID-19. This exhaustive review discusses the outcomes associated with COVID-19 in patients with advanced cirrhosis and in liver transplant recipients. We focus on the immunopathogenesis of COVID-19, its correlation with the pathogenesis of advanced liver disease, and the effect of immunosuppression in liver transplant recipients to provide insight into the outcomes of this unique patient population.