The development of direct-acting antiviral agents has revolutionized the treatment of hepatitis C by offering genuine prospects for a comprehensive cure of a chronic viral infection. This success can ...be traced to important scientific, clinical, and regulatory developments.
Chronic hepatitis C is a major cause of liver cirrhosis and hepatocellular carcinoma worldwide. Some 130 million to 170 million people, or about 3% of the world's population, are chronically infected with the hepatitis C virus (HCV). In the United States, chronic hepatitis C, the most common cause of liver-related death and reason for liver transplantation, recently eclipsed human immunodeficiency virus (HIV) infection as a cause of death. The development of direct-acting antiviral agents (DAAs) has revolutionized HCV treatment by offering genuine prospects for the first comprehensive cure of a chronic viral infection in humans. This success can be traced . . .
The advent of direct-acting antivirals (DAAs) has brought about a sudden renaissance in the treatment of chronic hepatitis C virus (HCV) infection with SVR rates now routinely >90%. However, due to ...the error-prone nature of the HCV RNA polymerase, resistance-associated substitutions (RASs) to DAAs may be present at baseline and can result in a significant effect on treatment outcomes and hamper the achievement of sustained virologic response. By further understanding the patterns and nature of these RASs, it is anticipated that the incidence of treatment failure will continue to decrease in frequency with the development of drug regimens with increasing potency, barrier to resistance, and genotypic efficacy. This review summarizes our current knowledge of RASs associated with HCV infection as well as the clinical effect of RASs on treatment with currently available DAA regimens.
Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated ...hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either a high-iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation, compared with healthy control subjects. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.
•Trf-LKO mice display iron-deficiency anemia, iron overload in tissues, and susceptibility to liver damage via ferroptosis.•Ferroptosis inhibition or deletion of Slc39a14 attenuated iron overload and CCl4-induced liver fibrosis in Trf-LKO.
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Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease worldwide. However, the molecular basis of how benign steatosis progresses to NASH is incompletely understood, which has ...limited the identification of therapeutic targets. Here we show that the transcription regulator TAZ (WWTR1) is markedly higher in hepatocytes in human and murine NASH liver than in normal or steatotic liver. Most importantly, silencing of hepatocyte TAZ in murine models of NASH prevented or reversed hepatic inflammation, hepatocyte death, and fibrosis, but not steatosis. Moreover, hepatocyte-targeted expression of TAZ in a model of steatosis promoted NASH features, including fibrosis. In vitro and in vivo mechanistic studies revealed that a key mechanism linking hepatocyte TAZ to NASH fibrosis is TAZ/TEA domain (TEAD)-mediated induction of Indian hedgehog (Ihh), a secretory factor that activates fibrogenic genes in hepatic stellate cells. In summary, TAZ represents a previously unrecognized factor that contributes to the critical process of steatosis-to-NASH progression.
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•TAZ/WWTR1 is increased in hepatocytes in human and mouse NASH liver•Hepatocyte TAZ silencing in steatosis blocks inflammation, cell death, and fibrosis•Hepatocyte TAZ silencing in NASH reverses inflammation, cell death, and fibrosis•Hepatocyte TAZ promotes fibrosis by inducing Ihh, a hepatic stellate cell activator
Hepatic fibrosis is a key feature of nonalcoholic steatohepatitis (NASH) affecting morbidity. Wang et al. investigate the underlying mechanisms for progression from benign steatosis to NASH and show that the transcription factor TAZ/WWTR1 is increased in mouse and human NASH. Silencing TAZ can prevent or reverse NASH features, notably fibrosis.
Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding of the mechanisms of NASH fibrosis, ...which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against liver fibrosis, but the mechanisms remain unknown. We now show that holo- or myeloid-specific Mertk targeting in NASH mice decreases liver fibrosis, congruent with the human genetic data. Furthermore, ADAM metallopeptidase domain 17 (ADAM17)-mediated MerTK cleavage in liver macrophages decreases during steatosis to NASH transition, and mice with a cleavage-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotes an ERK-TGFβ1 pathway that activates HSCs and induces liver fibrosis. These data provide insights into the role of liver macrophages in NASH fibrosis and provide a plausible mechanism underlying MERTK as a genetic risk factor for NASH fibrosis.
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•MerTK signaling in liver macrophages promotes liver fibrosis in NASH•Macrophage MerTK activates hepatic stellate cells in NASH by inducing TGF-β1•ATRA-induced MerTK cleavage blocks the TGF-b1-fibrosis pathway in steatosis•ATRA-induced MerTK cleavage becomes defective in NASH
Genome-wide association studies have indicated that MerTK is a risk factor for liver fibrosis in NASH with an unknown mechanism. Cai et al. discovered that MerTK signaling in liver macrophages, which is enhanced in NASH owing to suppression of its cleavage by ADAM17, promotes TGF-β1 production, HSC activation, and liver fibrosis in NASH.
Background and Aims
Coronavirus disease 2019 (COVID‐19), the illness caused by the SARS‐CoV‐2 virus, is rapidly spreading throughout the world. Hospitals and healthcare providers are preparing for ...the anticipated surge in critically ill patients, but few are wholly equipped to manage this new disease. The goals of this document are to provide data on what is currently known about COVID‐19, and how it may impact hepatologists and liver transplant providers and their patients. Our aim is to provide a template for the development of clinical recommendations and policies to mitigate the impact of the COVID‐19 pandemic on liver patients and healthcare providers.
Approach and Results
This article discusses what is known about COVID‐19 with a focus on its impact on hepatologists, liver transplant providers, patients with liver disease, and liver transplant recipients. We provide clinicians with guidance for how to minimize the impact of the COVID‐19 pandemic on their patients’ care.
Conclusions
The situation is evolving rapidly, and these recommendations will need to evolve as well. As we learn more about how the COVID‐19 pandemic impacts the care of patients with liver disease, we will update the online document available at https://www.aasld.org/about-aasld/covid-19-and-liver.
...patients who received more than one course of direct-acting antivirals were considered to have continuous exposure to direct-acting antivirals from the first course through to the last course, ...even though the first course of direct-acting antivirals might not have been associated with sustained virological response and there could have been a lag time between courses of direct-acting antivirals. ...patients with a history of decompensated cirrhosis and liver transplantation were excluded. ...they provide credence to the achievability of the goals set out by WHO, not only to eliminate HCV but also to substantially reduce its complications.7 Ramon Andrade 3Dciencia/Science Photo Library RTC reports grants to his institution from AbbVie, Gilead, and Merck for clinical trials of direct-acting antivirals for HCV, and from Gilead for assessment of long-term outcomes; and grants from Bristol-Myers Squibb, Roche, Janssen, and Boehringer Ingelheim, outside the area of work commented on here.
HCV and HIV co-infection is associated with accelerated hepatic fibrosis progression and higher rates of liver decompensation and death compared to HCV monoinfection, and liver disease is a leading ...cause of non-AIDS-related mortality among HIV-infected patients. New insights have revealed multiple mechanisms by which HCV and HIV lead to accelerated disease progression, specifically that HIV infection increases HCV replication, augments HCV-induced hepatic inflammation, increases hepatocyte apoptosis, increases microbial translocation from the gut and leads to an impairment of HCV-specific immune responses. Treatment of HIV with antiretroviral therapy and treatment of HCV have independently been shown to delay the progression of fibrosis and reduce complications from end-stage liver disease among co-infected patients. However, rates of sustained virologic response with PEG-IFN and ribavirin have been significantly inferior among co-infected patients compared with HCV-monoinfected patients, and treatment uptake has remained low given the limited efficacy and tolerability of current HCV regimens. With multiple direct-acting antiviral agents in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients, which incorporates data on fibrosis stage as well as potential drug interactions with antiretroviral therapy.
Background and Aims
Coronavirus disease 2019 (COVID‐19) leads to elevated liver biochemistries in approximately half of patients on presentation. To date, data are limited regarding the trend of ...liver biochemistries over the course of illness. We aimed to evaluate the trend, etiology, and outcomes associated with liver biochemistries in COVID‐19.
Approach and Results
A total of 60 patients with COVID‐19 were admitted between March 21 and March 28, 2020. The mean age was 57 years, 65% were male, and 28% were Hispanic. At the study conclusion, 6 patients were deceased, 28 were discharged, and 26 remained admitted. Patients who remained admitted were followed for a median of 12 days. Of 60 patients, 41 (69%) had at least one abnormal liver biochemistry on admission. Median aspartate aminotransferase (AST) was higher than alanine aminotransferase (ALT) at admission (46 vs. 30 U/L) and during the hospital course. Aminotransferases rose above normal in 54 (93%) patients, whereas alkaline phosphatase and total bilirubin elevations were rare. Ten (17%) patients developed aminotransferases more than 5 times the upper limit of normal. AST highly correlated with ALT throughout the illness course (r = 0.97; P < 0.0001), whereas correlations with markers of muscle injury and inflammation were weak. Statin use was common before (40%) and during admission (80%) at our center, with no difference in peak liver biochemistries between users and nonusers. No demographic or comorbid illness was associated with liver injury. Admission AST (69 vs. 49; P < 0.05), peak AST (364 vs. 77; P = 0.003), and peak ALT (220 vs. 52; P = 0.002) were higher in intubated patients.
Conclusions
AST‐dominant aminotransferase elevation is common in COVID‐19, mirrors disease severity, and appears to reflect true hepatic injury.
Summary Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in ...the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies.
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