Dr. Wells is Assistant Professor of Medicine (Gastroenterology), University of Pennsylvania School of Medicine, Philadelphia, PA.
Dr. Wells reports no conflicts of interest.
Release Date: 08/15/2007
Termination Date: 08/15/2010
Estimated time to complete: 1 hour(s).
Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
- Discuss current thinking about the mechanisms of fibrosis
- Discuss new modalities for diagnosing fibrosis
- Discuss evidence supporting the possibility of fibrosis regression
- Discuss new treatment options for fibrosis, and understand their relationship to concepts of regression.
Dr. Wells will discuss the unapproved use of Fibroscan® and MR elastography.
Liver fibrosis, like pathological fibrosis in other organs, has been termed "wound healing gone bad." Simply defined, it is the deposition of abnormal extracellular matrix (ECM) - scar tissue - in the chronically injured liver. The distribution of abnormal matrix can vary from periportal to pericentral. Similarly, the etiology of the chronic injury varies and can include chronic viral hepatitis (hepatitis B and C), alcohol abuse, non-alcoholic fatty liver disease (NAFLD), autoimmune disease, biliary obstruction, and congenital and metabolic anomalies. Nonetheless, fibrosis is a generic response: the underlying mechanisms are similar and the end result "architectural distortion with the formation of nodules, otherwise known as cirrhosis" is the same.
A fibrotic liver contains up to ten times as much total ECM as a normal liver. One of the first and most dramatic changes is the capillarization of the sinusoids, first described by Hans Popper in 1963, in which the sparse and loosely organized ECM of the normal sinusoids is replaced with an organized basement membrane. This is associated with profound changes in cell function, including dedifferentiation of hepatocytes and loss of fenestrations of the sinusoidal endothelial cells. Diffusion of soluble proteins and fluids between the sinusoidal blood and adjacent cells is impaired, and the synthetic and detoxification abilities of hepatocytes decrease. Later, as fibrosis progresses, dense bands of the rigid fibrillar collagens (collagens I and III) and other matrix molecules form. The mechanical changes and architectural distortion of the liver worsen, with the development of portal hypertension and the associated complications of end-stage liver disease.
Fibrosis and cirrhosis affect millions worldwide. In the United States alone, there are an estimated 400,000 people with cirrhosis, and the incidence will likely increase due to the epidemics of hepatitis C and NAFLD in this country. The incidence of deaths from end-stage liver disease due to alcohol abuse and hepatitis B infection remains high worldwide and there is yet no treatment for fibrosis or cirrhosis. Nevertheless, research in the past decade has shed new light on the mechanisms of fibrosis. New diagnostic tests and treatments are poised to enter the marketplace. The goal of this Cyberounds® is to introduce participants to new concepts in fibrosis that will enable them to better understand new tests and treatments in the future.
Mechanisms of Fibrosis
An Imbalance Between Matrix Synthesis and Degradation
ECM is synthesized continuously even in the normal liver. In fibrosis there is a shift in the quality of the ECM as well as an increase in the amount of ECM deposited. While ECM synthesis is normally balanced by ECM proteolysis (breakdown), and overall levels of ECM remain constant, in the diseased liver there is an imbalance between synthesis and breakdown. Although matrix proteolysis may increase (enabling migration of fibrogenic cells), it is surpassed by an increase in matrix synthesis, leading to net matrix deposition, or fibrosis (Figure 1).
Figure 1. Fibrosis Results from an Imbalance Between Synthesis and Degradation.
The Myofibroblast in Fibrosis
The key pathogenic cells in fibrosis are myofibroblasts, cells that express the α-smooth muscle isoform of actin (α-SMA; Figure 2). These cells are fibrogenic, secreting excessive amounts of abnormal matrix, and contractile, contributing to the hemodynamic changes seen in liver fibrosis.(1) They are highly proliferative, secrete many profibrogenic growth factors and may be proinflammatory, all leading to self-perpetuation of the fibrotic process.
Figure 2. Myofibroblasts in Culture Stained with α-smooth Muscle Actin (Red).
Note the actin arranged in stress fibers, which are contractile. Nuclei are stained blue.
Myofibroblasts in liver fibrosis originate from multiple precursor cells. The best known are hepatic stellate cells (HSC), the vitamin A-storing cells of the body, formerly called Ito cells or lipocytes. Emerging data suggest that other cells also undergo differentiation to myofibroblasts and contribute to fibrosis. These include cells from the bone marrow, hepatocytes, portal fibroblasts (PF) and biliary epithelial cells (BECs).(2),(3),(4),(5),(6) Because of their location in the portal tract, PFs and BECs may be particularly important in biliary (periportal) fibrosis. As compared to HSC, PFs and BECs differentiate in response to different stimuli and are, therefore, potentially attractive targets for disease-specific therapies.