The progression of chronic liver diseases (CLD), irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response as well as sustained activation of liver ...fibrogenesis and wound healing response. Liver fibrogenesis, is a dynamic, highly integrated molecular, cellular and tissue process responsible for driving the excess accumulation of extracellular matrix (ECM) components (i.e., liver fibrosis) sustained by an eterogeneous population of hepatic myofibroblasts (MFs). The process of liver fibrogenesis recognizes a number of common and etiology-independent mechanisms and events but it is also significantly influenced by the specific etiology, as also reflected by peculiar morphological patterns of liver fibrosis development. In this review we will analyze the most relevant established and/or emerging pathophysiological issues underlying CLD progression with a focus on the role of critical hepatic cell populations, mechanisms and signaling pathways involved, as they represent potential therapeutic targets, to finally analyze selected and relevant clinical issues.
Progressive accumulation of fibrillar extracellular matrix (ECM) in the liver is the consequence of reiterated liver tissue damage due to infective (mostly hepatitis B and C viruses), ...toxic/drug-induced, metabolic and autoimmune causes, and the relative chronic activation of the wound-healing reaction. The process may result in clinically evident liver cirrhosis and hepatic failure. Although cirrhosis is the common result of progressive fibrogenesis, there are distinct patterns of fibrotic development related to the underlying disorders causing the fibrosis. These different patterns of fibrogenic evolution are related to different factors and particularly: (1) the topographic localization of tissue damage, (2) the relative concentration of profibrogenic factors and (3) the prevalent profibrogenic mechanism(s). The mechanisms responsible for the fibrogenic evolution of chronic liver diseases can be summarized in three main groups: chronic activation of the wound-healing reaction, oxidative stress-related molecular mechanisms, and the derangement of the so-called 'epithelial-mesenchymal' interaction leading to the generation of reactive cholangiocytes and peribiliary fibrosis. Most of the knowledge on the cell and molecular biology of hepatic fibrosis derives from in vitro studies employing culture of activated hepatic stellate cells isolated from rat, mouse or human liver. It is now evident that other ECM-producing cells, i.e. fibroblasts and myofibroblasts of the portal tract and circulating 'fibrocytes', are likely to contribute to liver fibrosis. More recently, the attention is progressively shifting to the profibrotic microenvironment of the liver with increasing interest for the role of immune cells and specific subsets of macrophages regulating the progression or the regression of fibrosis, the role of intestinal microbiota and the influence of tissue stiffness. Other major areas of development include the role of tissue hypoxia and the establishment of an anaerobic proinflammatory environment and the influence of epigenetic modification in conditioning the progression of fibrosis.
The possibility that epithelial–mesenchymal transition (EMT) could contribute to hepatic fibrogenesis in chronic liver diseases as reported in other organs, particularly the kidney, reinforced the ...concept that activated hepatic stellate cells were not the only key players in the hepatic fibrogenic process and that other cell types, either hepatic (i.e. portal fibroblast) or extrahepatic (bone marrow-derived cells and circulating fibrocytes) could contribute to this process. The possibility of the rapid mobilization of a large amount of fibrogenic cells by EMT after liver tissue injury made this phenomenon a relevant and suitable target for anti-fibrogenic strategies. Following an initial enthusiasm for the discovery of this novel pathway in fibrogenesis and the publication of a several highly quoted papers, more recent research has started to cast serious doubts upon the real relevance of this phenomenon in human fibrogenetic disorders. The debate on the authenticity of EMT or at least on its real contribution to the fibrogenic process has become very animated, sometimes reaching levels of “religious” integralism. The overall result is a general confusion on the meaning and on the definition of several key aspects. The aim of this article is to analyze and discuss the evidence supporting or confuting this possibility in order to reach reasonable and useful conclusions.
Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been ...approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell–cell interactions and etiology‐specific elements of fibrogenesis and their link to disease‐specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver’s endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease. Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.
The development of portal hypertension is a common consequence of chronic liver diseases leading to the formation of esophageal and gastric varices responsible for variceal bleeding, associated with ...a high mortality rate, as well as other severe complications such as portosystemic encephalopathy and sepsis. Measurement of hepatic venous pressure gradient (HVPG) and upper GI endoscopy are considered the gold standards for portal hypertension assessment in patients with cirrhosis. However, both types of investigation are invasive and HVPG measurement is routinely available and/or performed with adequate standards only in expert centres. There is thus a need for non invasive methods able to predict, with acceptable diagnostic accuracy, the progression of portal hypertension toward the levels of clinically significant (i.e. HVPG ⩾10 mmHg) and severe (HVPG ⩾12 mmHg) as well as the presence and the size of oesophageal varices. Transient elastography (TE) is a novel non invasive technology that allows measuring liver stiffness and that has gained popularity over the past few years. Although TE has been initially proposed to assess liver fibrosis, a good correlation has been reported between liver stiffness values and HVPG as well as the presence of oesophageal varices, suggesting that it could be an interesting tool for the non invasive evaluation of portal hypertension. This review is aimed at discussing the advantages and limits of TE and the perspectives for its rationale use in clinical practice for the management of patients with portal hypertension.
A two-step process, in which circulating levels of amyloid P are reduced and then anti–serum amyloid P antibody is given to activate macrophage clearance mechanisms of tissue deposits, appears to ...reduce amyloid deposits in liver and some other organs.
In systemic amyloidosis, the extracellular deposition of normally soluble plasma proteins as insoluble amyloid fibrils damages the structure and function of tissues and organs.
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Current treatment consists of support or replacement of failing organs and measures to reduce the abundance of the amyloid fibril precursor protein.
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A sufficient reduction of precursor supply arrests the accumulation of amyloid and can reduce morbidity and mortality. However, amyloid regression is very slow and often does not occur at all, in contrast to the usually swift clearance of other extracellular debris and efficient tissue remodeling — for example, after trauma. At least 65% . . .
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.
The stratification of cirrhosis Maurice, James; Pinzani, Massimo
Hepatology research,
20/May , Volume:
50, Issue:
5
Journal Article
Peer reviewed
Open access
Cirrhosis is traditionally seen as an irreversible stage of chronic liver disease although its clinical course may last several years. Overall, the clinical management of patients with cirrhosis is ...based on the observation of clinical events mostly related to complications of portal hypertension. Each event of cirrhosis decompensation has clear prognostic implications although it is not precisely predictable. In practice, the advancement in the knowledge of the mechanisms responsible for disease progression is not yet translated in clinical tools allowing the stratification of the cirrhotic stage according to pathophysiological mechanisms. This article provides a review of the main clinical and histopathological features of liver cirrhosis that are relevant for its clinical stratification together with the advancements provided by the introduction of non‐invasive measures of portal hypertension. Other clinical aspects that have a major impact on the quality of life and the possibility of liver transplantation are also discussed.
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