Summary Liver fibrosis and in particular cirrhosis have become major endpoints in clinical trials of patients with chronic liver diseases. Here, viral hepatitis, alcoholic and non-alcoholic ...steatohepatitis have become the major etiologies. We have made great progress in our understanding of the mechanisms and the cell biology of liver fibrosis and have already made the transition from preclinical testing of antifibrotic agents and strategies towards clinical translation. There continues to be an urgent need for specific antifibrotic therapies, despite the advent of highly potent antiviral agents that can even induce regression of advanced fibrosis. This review addresses central mechanisms and cells to be targeted, current antifibrotic drug trials, and the state of non-invasive biomarker development that is key to rapid clinical progress and to a personalized treatment of fibrosis.
Cirrhosis has become the major liver-related clinical endpoint in non-alcoholic steatohepatitis (NASH). However, progression to cirrhosis is less predictable in NASH than in other chronic liver ...diseases. This is due to the complex and multifactorial aetiology of NASH, which is determined by lifestyle and nutrition, multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Thus, modest changes in these cofactors can also induce fibrosis regression, at least in patients with precirrhotic liver disease. Fibrogenesis in NASH correlates with, but is indirectly coupled to, classical inflammation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte lipoapoptosis is a key driving force of fibrosis progression, activated hepatic stellate cells, myofibroblasts, cholangiocytes, macrophages and components of the pathological extracellular matrix are major fibrogenic effectors and thus pharmacological targets for therapies aimed at inhibition of fibrosis progression or induction of fibrosis reversal. The advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH will improve detection, stratification and follow-up of patients with progressive NASH . These non-invasive tools will also promote the clinical development of antifibrotic drugs, by permitting the design of lean proof-of-concept studies, and enabling development of a personalised antifibrotic therapy for patients with rapid fibrosis progression or advanced disease.
Cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) produced by them have been recognized as key players in cancer biology and emerged as important targets for cancer treatment and ...drug discovery. Apart from their presence in stroma rich tumors, such as biliary, pancreatic and subtypes of hepatocellular cancer (HCC), both CAF and certain ECM components are also present in cancers without an overt intra-tumoral desmoplastic reaction. They support cancer development, growth, metastasis and resistance to chemo- or checkpoint inhibitor therapy by a multitude of mechanisms, including angiogenesis, ECM remodeling and active immunosuppression by secretion of tumor promoting and immune suppressive cytokines, chemokines and growth factors. CAF resemble activated hepatic stellate cells (HSC)/myofibroblasts, expressing α-smooth muscle actin and especially fibroblast activation protein (FAP). Apart from FAP, CAF also upregulate other functional cell surface proteins like platelet-derived growth factor receptor β (PDGFRβ) or the insulin-like growth factor receptor II (IGFRII). Notably, if formulated with adequate size and zeta potential, injected nanoparticles home preferentially to the liver. Several nanoparticular formulations were tested successfully to deliver dugs to activated HSC/myofibroblasts. Thus, surface modified nanocarriers with a cyclic peptide binding to the PDGFRβ or with mannose-6-phosphate binding to the IGFRII, effectively directed drug delivery to activated HSC/CAF in vivo. Even unguided nanohydrogel particles and lipoplexes loaded with siRNA demonstrated a high in vivo uptake and functional siRNA delivery in activated HSC, indicating that liver CAF/HSC are also addressed specifically by well-devised nanocarriers with optimized physicochemical properties. Therefore, CAF have become an attractive target for the development of stroma-based cancer therapies, especially in the liver.
Summary Liver fibrosis results from an excessive wound healing response in most chronic liver diseases, such as hepatitis C. Despite great advances in antiviral therapy in recent years, progressive ...liver fibrosis remains a major problem for patients with recurrent hepatitis C after liver transplantation. Liver biopsy remains a central tool in the management of HCV-positive liver transplant recipients, but reliable non-invasive methods for the assessment of liver fibrosis, such as ultrasound elastography, are increasingly being incorporated in the management of post-transplant patients, helping predict prognosis, guide treatment decisions, and stratify patients for emerging antifibrotic therapies. In this manuscript, we will review the natural history as well as tools to monitor fibrosis progression in the HCV-positive liver transplant recipient, the mechanisms underlying rapid fibrosis progression in up to 30% of these patients, the effect of antiviral therapies and highlight promising antifibrotic approaches.
Liver fibrosis and in particular cirrhosis are the major causes of morbidity and mortality of patients with chronic liver disease. Their prevention or reversal have become major endpoints in clinical ...trials with novel liver specific drugs. Remarkable progress has been made with therapies that efficiently address the cause of the underlying liver disease, as in chronic hepatitis B and C. Highly effective antiviral therapy can prevent progression or even induce reversal in the majority of patients, but such treatment remains elusive for the majority of liver patients with advanced alcoholic or nonalcoholic steatohepatitis, genetic or autoimmune liver diseases. Moreover, drugs that would speed up fibrosis reversal are needed for patients with cirrhosis, since even with effective causal therapy reversal is slow or the disease may further progress. Therefore, highly efficient and specific antifibrotic agents are needed that can address advanced fibrosis, i.e., the detrimental downstream result of all chronic liver diseases. This review discusses targeted antifibrotic therapies that address molecules and mechanisms that are central to fibrogenesis or fibrolysis, including strategies that allow targeting of activated hepatic stellate cells and myofibroblasts and other fibrogenic effector cells. Focus is on collagen synthesis, integrins and cells and mechanisms specific including specific downregulation of TGFbeta signaling, major extracellular matrix (ECM) components, ECM-crosslinking, and ECM-receptors such as integrins and discoidin domain receptors, ECM-crosslinking and methods for targeted delivery of small interfering RNA, antisense oligonucleotides and small molecules to increase potency and reduce side effects. With an increased understanding of the biology of the ECM and liver fibrosis and an improved preclinical validation, the translation of these approaches to the clinic is currently ongoing. Application to patients with liver fibrosis and a personalized treatment is tightly linked to the development of noninvasive biomarkers of fibrosis, fibrogenesis and fibrolysis.
•Liver fibrosis is a dynamic process, and even advanced fibrosis is reversible•Myofibroblasts, cholangiocytes and macrophages are central effectors of fibrosis•ECM proteins, receptors and proteases are key targets for antifibrotic therapies•Small molecules, siRNA, antisense oligos and nanoparticular delivery have entered the clinic•Novel noninvasive tools permit rapid clinical testing and a personalized medicine
Celiac disease has become one of the best-understood HLA-linked disorders. Although it shares many immunologic features with inflammatory bowel disease, celiac disease is uniquely characterized by ...(1) a defined trigger (gluten proteins from wheat and related cereals), (2) the necessary presence of HLA-DQ2 or HLA-DQ8, and (3) the generation of circulating autoantibodies to the enzyme tissue transglutaminase (TG2). TG2 deamidates certain gluten peptides, increasing their affinity to HLA-DQ2 or HLA-DQ8. This generates a more vigorous CD4+ T-helper 1 T-cell activation, which can result in intestinal mucosal inflammation, malabsorption, and numerous secondary symptoms and autoimmune diseases. Moreover, gluten elicits innate immune responses that act in concert with the adaptive immunity. Exclusion of gluten from the diet reverses many disease manifestations but is usually not or less efficient in patients with refractory celiac disease or associated autoimmune diseases. Based on the advanced understanding of the pathogenesis of celiac disease, targeted nondietary therapies have been devised, and some of these are already in phase 1 or 2 clinical trials. Examples are modified flours that have been depleted of immunogenic gluten epitopes, degradation of immunodominant gliadin peptides that resist intestinal proteases by exogenous endopeptidases, decrease of intestinal permeability by blockage of the epithelial ZOT receptor, inhibition of intestinal TG2 activity by transglutaminase inhibitors, inhibition of gluten peptide presentation by HLA-DQ2 antagonists, modulation or inhibition of proinflammatory cytokines, and induction of oral tolerance to gluten. These and other experimental therapies will be discussed critically.
Non‐alcoholic fatty liver disease (NAFLD) refers to a disease spectrum, ranging from mere hepatic steatosis to hepatic necroinflammation (NASH, non‐alcoholic steatohepatitis). NASH often leads to ...fibrosis, which can progress to cirrhosis with a high risk of liver failure and hepatocellular carcinoma. The course of NAFLD is highly variable, and only a minority of patients (2–3%) progress to end‐stage liver disease. However, due to a dramatic increase of the risk factors for NAFLD, that is obesity and insulin resistance/type 2 diabetes, that affect 15–30% and 7–15% of subjects, in most industrialized countries, respectively, NAFLD has become the most frequent liver disease and is even considered a pace setter of the metabolic syndrome. Sedentary lifestyle, modern Western nutrition, and genetic predispositions have been identified as major causes of NAFLD. These lead to liver injury via insulin resistance and an excess of free fatty acids in hepatocytes, resulting in oxidant stress and lipotoxicity that promote the activation of intracellular stress kinases and apoptosis or necroapoptosis (NASH). The damaged hepatocytes directly trigger inflammation and fibrogenesis, but can also lead to the emergence of fibrogenic progenitor cells. Moreover, NASH is linked to inflammation in peripheral adipose tissues that involves mainly macrophages and humoral factors, such as adipokines and cytokines. The most efficient treatment is by weight loss and exercise, but (adjunctive) pharmacological strategies are urgently needed. Here, we highlight the aspects of NAFLD epidemiology and pathophysiology that are beginning to lead to novel pharmacological approaches to address this growing health‐care challenge.
Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality ...worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH.
Summary While preclinical development of potential anti-fibrotics is far advanced, with numerous pharmacological targets and promising agents, almost none has entered clinical validation. Reasons are ...manifold, including the usually slow progression of liver fibrosis, requiring high numbers of well-stratified patients undergoing long-term treatment when conventional liver biopsy based parameters or hard liver-related endpoints are used. Importantly, there is a notorious lack of sensitive and specific surrogate markers or imaging technologies for liver fibrosis progression or regression that would permit a rapid clinical screening for potential anti-fibrotics. Nonetheless, in view of an urgent need for anti-fibrotics that positively impact morbidity and mortality from chronic liver diseases, the field is now moving more quickly towards clinical translation. This development is driven by thoughtful preclinical validation, a better study design and improved surrogate readouts using currently available methodologies. Moreover, upcoming novel biomarkers and imaging technologies will soon permit a more exact and efficient assessment of fibrosis progression and regression.
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