I would say so; however, the degree of inflammation probably depends on the underlying etiology or cause of the liver fibrosis, e.g., hepatitis C infection, autoimmune hepatitis, alcoholic cirrhosis, drug-induced liver disease, etc,

Hi Dhastagir Sheriff and Emilio Gonzalez ·

Thanks for your information

Liver fibrosis is the sequale of inflammatory response inside the liver tissue. Many causes will induce inflammation followed by fibrosis through stellate cells activation and eventually would progress to cirrhosis (advanced fibrosis). Stellate cells are activated in response to many inflammatory mediators released from the surrounding inflammatory background.

Liver fibrosis may the considered the long term consequence of chronic inflammation. However, often the two phenomenon coexist. A high degree fibrosis indiicate a late stage of the disorders and a severe impairement of liver function with a high risk of compliacation and, often, represent the indication for liver transplantation. The sequence inflammaion-fibrosis may be seen in many other organs, such as lung, intestine (Crohn's disease), arterial vessels etc. I think that the availability of Fibroscan may help to follow the process and is a very useful instrument. It is commonly used to detect the presence and entity of liver fibrosis, but investigations using a similar criterion are used in cardiology for atherosclerosis classification or predisposition identification. In conclusion, organ fibrosis as terminal step of a long standing inflammation is not only a biological problem of scientific speculation, but also an interesting topic for the clinical practice.

This assumption cannot be made unequivocally. Liver inflammation and fibrosis are distinct processes, and they do not always co-occur. There are plenty of examples where inflammation occurs in the absence of fibrosis. There are far fewer examples of fibrosis in the absence of inflammation, but they do exist. For example, transgenic mice overexpressing either PDGF-B or -C in the liver develop fibrosis (i.e. collagen deposition and remodeling of the extracellular matrix) in the absence of inflammation (PubMed IDs: 16842882 and 15728360). There are also cases where inflammation and fibrosis occur together, but the inflammation is subsequently resolved while the fibrosis remains (e.g. PubMed ID: 12475903). Scott Friedman at Mount Sinai School of Medicine has published some outstanding reviews on the topic of liver fibrosis and the mechanisms by which it may contribute to liver cancer directly.

Nothing is unequivocally in Medicine and every concept may be changed by successive researchs. Nevertheless, in the clinical practice liver inflammation and fibrosis coexist in most known diosrders. Inflammation may decrese with the progression of fibrosis is a very old even isf still actual concept. However, thank you for the information about animal models which develop fibrosis in the absence of inflammation: they may open new scientific herizons, but what is their clinical meaning at the moment?

That's a good point, there's very little in science or medicine that is unequivocal. Still, I thought it important to emphasize the distinction here and the fact that these are separate conditions that can occur independently. The concept that inflammation can subside in the presence of sustained fibrosis when both were initially present may be old, but that doesn't diminish its importance. As for clinical meaning, I believe that it's important to understand as much as we can about the physiological and molecular mechanisms that underlie disease processes. Though fibrosis rarely occurs in patients in the absence of inflammation, it may be an important mechanistic driver of tumorigenesis (independently of or in coordination with inflammation). Thus, it could represent a process to target therapeutically to prevent or treat cancer. The ability to separate distinct aspects of disease in different animal models is a major advantage that allows specific hypotheses to be tested and helps to eliminate confounding factors. To dismiss a model as irrelevant because it doesn't completely recapitulate the human disease is to discard a wealth of valuable information. Countless animal models have proven this point. Clearly it is still critical to use the data gained from these models as a complementary approach to direct analysis of human samples and other models that more fully recapitulate human disease. As an answer to the original question "Can we consider liver fibrosis as an inflammatory disease of the liver?", the ultimate answer is "not necessarily". In many cases this is so, but there are functions beyond the inflammation through which fibrosis can directly promote further liver disease. Here's a great review on the topic: Hepatology. 2012 Aug;56(2):769-75.

But isn't inflammation a necessary precursor to fibrosis?

It is years or possibly decades before the fibrotic process becomes clinically apparent except for paediatric liver disease, drug-induced liver disease and viral hepatitis (when accompanied with immunosuppression). There are two mechanisms that regulate hepatic fibrosis-necrosis and apoptosis. Necrosis is considered to be a classical inflammatory and fibrogenic response where there is a perturbation of normal liver homeostasis. Necrotic liver injury is usually associated with the infiltration of inflammatory cells even in the absence or before the arrival of extrahepatic cells; the liver contains sufficient resident macrophages such as Kupffer cells and natural killer cells to initiate inflammation locally (Friedman et al 2004).

Fibrosis is the accumulation of scar tissue in the extracellular matrix resulting from liver damage. Matrix proteins such as collagens make up the fibrous material. This is a dynamic process that can be reversed when matrix metaloproteases (MMPs) are expressed, breaking down matrix proteins. Fibrotic material is deposited between hepatocytes and circulating blood. It is through fibrosis that the liver seals off injured areas preventing further damage caused by inflammation. The hepatocytes that become trapped within the fibrosis die as they lose their blood supply and are starved of oxygen and nutrients leading to further fibrosis (Yang et al 2003).

Although necrosis is the classical inflammatory and fibrogenic stimulus, apoptotic liver damage or programmed cell death has also been implicated as a profibrogenic stimulus. Apoptotic fragments released from hepatocytes are fibrogenic for cultured stellate cells and FAS-mediated hepatocyte apoptosis in vivo is also fibrogenic (Canbay et al 2002, 2003).

Sinusoidal endothelial cells (SEC) are normally fenestrated and allow solutes to be transported in both directions between blood and parenchymal cells. As pro-inflammatory effectors invade they lose their fenestration on injury and contribute towards intrahepatic apoptosis. Together with stellate cells, the SECs express proinflammatory molecules (ICAM-1, VEGF, and adhesion molecules) activating angiogenic pathways leading to fibrosis (LeCouteur et al 2003). Stellate cells may contribute towards the intrahepatic apoptosis of T cells (Kobayashi et al 2003).

Risk factors for fibrosis can be acquired or genetic. Males are at increased risk and acquired risk factors include adiposity and alcohol intake. Genetic factors have been identified in animal studies but these now are being investigated in human studies (Bataller et al 2003).

Regression of fibrosis requires that activated hepatic stellate cells are cleared through apoptosis; that tissue inhibitors of metalloproteinase-1 (TIMP-1) are downregulated and matrix metaloproteases are allowed to break down the fibrotic septae (Murphy et al 2002).

The progression of a normal lobular structure to a cirrhotic septum with cellular changes from quiescent to activated hepatocytes involves the activation of Kupffer cells and hepatic stellate cells (HSC) during the development of cirrhosis. (Ramadori and Saile 2004a)

Activation of the hepatic stellate cell is required for fibrogenesis. The hepatic stellate cell stores vitamin A but in response to injury, synthesizes collagen along with other extracellular matrix proteins. Damaged hepatocytes and liver sinusoidal endothelial cells activate hepatic stellate cells (Guyot et al 2005).

Immune responses also activate fibrogenesis through their patterns of cytokine release. Fibrogenesis can be modulated by T cells through the release of cytokines such as TGF-beta, Platelet derived growth factor (PDGF) and endothelin. In murine studies it has been found that Th1 responses result in less fibrogenesis than Th2 responses. IFN-gamma a product of Th1 differentiation appears to inhibit the process of fibrosis and TGF-beta activity. CD8+ T cell also have emerged as potential profibrogenic cells (Friedman 2004).

Recently, researchers have discovered the importance of non-parenchymal cells in the genesis of hepatocellular injury. Neutrophils are part of the inflammatory response, especially in phagocytosis and killing of pathogenic organisms but during the antiviral response can also damage host tissue. The production of reactive oxygen species is one of the ways that neutrophils kill pathogenic organisms. Radical scavengers such as superoxide dismutase may be important in the protection of hepatocytes when exposed to neurophil attack (Varani et al 1985).

Fibrosis can be the result of oxidative stress, or extracellular release of signalling molecules which may be from endocrine, paracrine or autocrine mechanisms. Oxidative stress mediated necrosis leads to stellate cell activation.

Stellate cells can also be infected by HCV and non-structural and core proteins induce stellate cell proliferation and the release of pro-inflammatory signals (Bataller and Brenner 2005).

The inflammatory response plays an important role in driving fibrogenesis, since persistent inflammation almost always precedes fibrosis. Activated HSCs secrete inflammatory chemokines, interact directly with immune cells through expression of adhesion molecules (Hellerbrand et al., 1996), and modulate the immune system through antigen presentation (Bomble et al., 2010). Therefore, a positive feed-back loop exists in which inflammatory and fibrogenic cells stimulate each other in amplifying fibrosis.

Immune activation also provokes fibrosis through signaling in response to bacterial lipopolysaccharide (LPS), a ligand for the TLR4 receptor, which is expressed on both macrophages and HSCs (Pradere et al., 2010).

Since angiotensin II and it's receptor are involved in development of fibrosis, why are ARB and ACE inhibitors not routinely used to prevent development of fibrosis?

If there are strong evidences, a clinical trial may be proposed and performed to verify the appropriateness of this therapeutic attempt.