الفهرس 
Definition of hepatic fibrosisOnly 14 pages are availabe for public view
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Abstract
Despite intensive experimental studies, the clinical opportunities for patients with fibrosing liver diseases have not yet significantly improved. It is expected that increasing knowledge of new pathogenetic mechanisms, which complement the ‘canonical principle’ of fibrogenesis, will have a beneficial effect on the translation to clinical medicine. It is now evident that the heterogeneous pool of (myo-) fibroblasts originates from the EMT of cholangiocytes and most likely of hepatocytes, from the influx of bone marrow– derived fibrocytes into the damaged liver tissue and from differentiation of a subgroup of circulating monocytes to fibroblasts after homing in the damaged tissue.
These processes offer innovative diagnostic and therapeutic options. As an example, modulation of the TGF-β/BMP-7 ratio changes the rate of EMT and by this progression of fibrosis. Over-expression of BMP-7 or application of recombined BMP-7 have a sustained antifibrotic effect. In addition, the determination of some of these parameters and of connective tissue growth factor (CTGF) in serum might provide information on fibrogenic activity. Thus, the pathogenetic road map of fibrosis has not (yet?) changed, but newly discovered backstreets now establish a much more complex network of interacting pathways radiating to systemic responses.
In general, liver biopsy still represents the gold standard for the evaluation of liver fibrosis. However, there are inherent limitations, such as the risk to the patient, sampling errors, and inter- and intraobserver variations in the interpretation of the biopsy results. In recent years, interest in identifying and describing liver fibrosis by using noninvasive, surrogate markers measurable in the serum has been increasing. The ideal marker should be specific for liver fibrosis, provide accurate staging, and not be influenced by comorbidities, and it should be sensitive, reproducible, and cost effective.
Many studies investigated the applicability of serum markers reflecting matrix deposition or degradation in the liver, including hyaluronan, laminin, type IV collagen, MMPs, TIMP-1, and combinations of these markers. Of these markers, hyaluronan seems to have a sensitivity and specificity of 86%–100% and 88%, respectively. Hyaluronan is secreted by activated HSCs and directly excreted to the sinusoids; therefore, serum levels reflect the activity state of HSCs. The diagnostic value of the other markers varies greatly from one study to another with a wide range of sensitivity. Another possible problem is that these markers may not be disease-specific, as increased values are also reported in autoimmune diseases, renal disease, pancreatitis, and lung fibrosis. Recently, data based on the Hepatitis C Long-term Treatment against Cirrhosis (HALT-C) trial subjects showed that a three-variable model consisting of serum hyaluronan, TIMP-1, and platelet count was better than other published models based on routine laboratory tests in identifying cirrhosis in patients with hepatitis C.
Further validation of these studies is needed, including comparison with other serum fibrosis markers, such as FibroTest and Hepascore. An exciting new method is the measurement of the proteolytic neoepitope of the caspase substrate cytokeratin 18 in the sera of patients with chronic liver disease, as a surrogate marker of caspase activity and apoptosis in the liver. In patients with hepatitis C or nonalcoholic steatohepatitis, this test yielded good results with sensitivity of up to 85.7% and specificity of 99.9%. Larger studies are under way to confirm these observations.
The further approach to detect fibrosis is based on routinely performed blood tests, with the aim of identifying alterations in liver synthetic function. Frequently, included markers are platelet count, transport proteins, bilirubin, ECM parameters, coagulation panel, and tests indicating hepatocellular damage, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). These tests can be compiled into either biochemical scores or biomarker panels generated by various statistical methods.
The best known are the aspartate aminotransferase-to-platelet ratio index (APRI), FibroTest, and Forns’ index. The most widely used noninvasive test is the FibroTest. It has the advantage of classifying all stages of fibrosis, but, on the other hand, it uses three rather uncommon parameters and requires laboratory standardization. APRI and Forns’ index are based on routine blood tests performed in each patient with liver disease. By combining the sequential algorithms of APRI, Forns’ index, and FibroTest, diagnostic performance can be signifycantly improved, resulting in a reduction of liver biopsies by 50%–70% in patients with hepatitis C virus (HCV). Although serum markers are emerging as potentially useful tools for assessing liver fibrosis, the major pitfall of all currently available markers is their lack of ability to reflect small changes in the early stages of fibrosis.
The improved understanding of mechanisms underlying hepatic fibrosis makes effective antifibrotic therapy an emerging reality. However, treatment will remain a challenging task, and thus far no drugs have been approved as antifibrotic agents in humans. Therapies will have to be well tolerated over decades, with good targeting to the liver and few adverse effects on other tissues. Combination therapies may prove synergistic rather than additive, but agents must first be tested individually to establish safety and “proof of principle”. It is uncertain whether antifibrotic therapies will require intermittent or continuous administration.
For putative agents, evidence of a direct antifibrotic effect must be established in experimental models rather than by only an indirect effect by abrogating the injury. Candidate therapies must be effective in a liver that is already damaged— as in clinical liver disease—rather than only before the onset of injury. Antifibrotic therapies also carry the theoretical concern that inhibiting the scarring response will prevent the encapsulation of injured regions, leading to extension of tissue damage. In reality, however, antifibrotic therapies only need to downregulate the scar response to be effective, and in patients with cirrhosis it is the scarring, not injury, that usually leads to liver failure.