الفهرس 
الملخص العربى
The Nature of the Hepatic ScarOnly 14 pages are availabe for public view
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Abstract
Hepatic fibrosis is a common response to chronic liver injury due to many causes, including alcohol, persistent viral and helminthic infections, and hereditary metal overload. Hepatic fibrosis results of accumulation of extracellular matrix (ECM) in response to acute or chronic liver injury. Fibrogenesis represents a wound healing response to injury, and ultimately leads to cirrhosis. Cirrhosis is the end-stage consequence of fibrosis of the hepatic parenchyma, that may lead to altered hepatic function.
In general, the molecular composition of the scar tissue in cirrhosis is similar regardless of etiology, and resembles that of other parenchymal scarring (e.g. kidney), consisting of the extracellular matrix constituents, collagen types I and III (i.e. ‘fibrillar’collagens), sulfated proteoglycans, and glycoproteins. Cirrhotic liver may contain up to six times more collagen and proteoglycan than a healthy organ. Although overall increases in the amount of hepatic matrix are important, of equal importance are the early changes in the composition of the matrix within the subendothelial space of Disse. Liver fibrosis is associated with the replacement of the normal low-density matrix with a high-density matrix.
Following liver injury of any etiology, stellate cells undergo a process known as ‘activation’. Quantitative and qualitative changes in activity of MMPs and their inhibitors play a vital role in extracellular matrix remodeling in liver fibrogenesis.
Although repeated assessment of liver histology is required in the management, liver biopsy is potentially associated with serious complications, and cannot be repeated frequently for ethical reasons. A suitable noninvasive marker for assessing the extent of liver fibrosis and necroinflammation seems to be of great clinical benefit for judging the clinical status and prognosis of patients.
MMP-1:
It acts on collagen types I, II, III, VII, X and gelatins. The activity of MMP-1 is needed to ensure normal metabolism of hepatocytes
Interstitial collagenase is also considerd a key enzyme involved in the degradation of fibrosis because of the predominance of collagens type I and III in the fibrotic liver. So, the expression of interstitial collagenase in the fibrous liver may be important from the standpoint of ameliorating liver fibrosis because MMP-1 activity is necessary to initiate collagen degradation
In studies undertaken to measure interstitial collagenase activity in liver fibrosis, a general pattern appeared; initially there is a reversible phase with active matrix remodelling and detectable collagenase activity. In late disease, fibrosis becomes irreversible, and, at this point, collagenase activity falls.
Other studies showed that the correlation of serum MMP-1 level with the degree of necroinflammation was weak, and the efficiency of serum MMP-1 test was poor for diagnosing the grading
On the other hand, serum levels of MMP-1 analysed in patients with biliary atresia to evaluate their clinical usefulness for assessing progressive fibrosis in biliary atresia patients; MMP-1 levels were significantly decreased compared with controls, especially in end-stage patients.
MMP-2:
MMP-2 is mainly secreted from activated hepatic stellate cells in liver during the process of inflammation and invasion. It can act on gelatin type І, collagen types IV, V, VII, X and elastin. MMP-2 is capable also of cleaving native type IV and V collagens. The expression of MMP-2 has been correlated with the metastatic state, and are believed to influence the ability of a cell to invade and metastasize due to their ability to degrade basement membrane type IV collagen
Progelatinase A (ProMMP-2) is activated at the surface of cells in a trimolecular interaction, that involves the formation of a complex with a transmembrane molecule (membrane type1-MMP ”MT1-MMP”, also known as MMP-14) and TIMP-2.
Activated MMP-2 is responsible for decomposion of type ІV collagen in the basement, resulting in broken micro-circumstances of hepatic stellate cells and promoting hepatic stellate cells to activate, proliferate and migrate and a process that is involved in the early steps of tissue remodeling that is characteristic of chronic liver diseases.
Several studies concluded that increase in serum type IV collagen and MMP-2 levels in serum are closely associated with the progress of hepatic fibrosis in chronic liver disease. The authors also demonstrated that the ratio between type IV collagen and MMP-2 levels was markedly elevated in liver cirrhosis, compared with chronic inactive hepatitis and chronic active hepatitis, presuming that production of type IV collagen exceeds degradation in liver cirrhosis, leading to accumulation of extracellular matrix during hepatic fibrogenesis.
A further reliable fibrotic marker for detection of the course of chronic hepatitis C was tried by the use of MMP-2/TIMP-1 ratio. There was decline in the ratio that was attributed to the increase in circulating TIMP-1 concentrations. When correlating the calculated ratios with histological data, it was found that the MMP-2/TIMP-1 ratio significantly correlates to both inflammatory activity and the extent of fibrosis.
MMP-9:
MMP-9 (gelatinase B) is one of the gelatinases subfamily of proteinases. They degrade gelatin and thus are named gelatinases. Gelatinases are characterized by their ability to degrade basement membrane collagen IV and so, are also known as type IV collagenases.
Serum MMP-9 levels were lower in patients with liver cirrhosis as compared to patients with chronic liver disease without cirrhosis and healthy controls. Moreover, it was found that MMP-9 decreased with progression of liver disease and correlated with changes detected in serum bilirubin, albumin and prothrombin time.
The levels were significantly higher in HCC patients with macroscopic portal venous invasion than those without the invasion.
TIMPs:
Hepatic TIMPs levels could reflect the rate of collagen accumulation and could be used to predict prognosis in chronic liver disease. On the other hand, such proteins being secretory proteins and can act extracellularly in the matrix, it may easily diffuse in the blood and the measurement of their serum levels could be useful for assessing the progress of liver diseases.
TIMP-1:
TIMP-1 could inhibit most of MMPs by integrating them individually to form a complex. Excess production of TIMPs relative to MMPs contributes to progression of liver fibrosis, whereas ECM breakdown could be enhanced by either a reduction in synthesis of TIMPs or an increase in the expression of MMPs
In chronic liver diseases and in animal models of liver fibrosis, significant increases in TIMP-1 expression have been observed and this in turn would help interstitial fibrils to accumulate. Therefore, TIMP-1 has been considered as a useful marker for hepatic fibrosis.
Circulating TIMP-1 and the MMP-2/TIMP-1 ratio correlated to the inflammatory activity in liver biopsies, but only the circulating MMP-2/TIMP-1 ratio also correlated with the degree of fibrosis.
Overexpression of TIMP-1 in TIMP-Tg mouse model without hepatic stellate cell activation did not induce fibrosis development or ECM remodeling, suggesting that TIMP-1 did not affect initiation of fibrosis. However, it significantly promoted fibrosis development upon fibrotic stimulation. In other words, TIMP-1 showed a strong activity that promoted liver fibrosis development under the condition of HSC activation but not in the quiescent stage. On the other hand, overexpression of TIMP-1 in TIMP-Tg significantly suppressed spontaneous liver fibrosis resolution associated with down-regulation of the MMP activity and upkeep of the HSC activation.
TIMP-2:
TIMP-2 has a very specific interaction with MMP-2. TIMP-2 can bind to progelatinase A (ProMMP-2), and prevent its conversion to the active form. In addition, it can inhibit the active form of MMP-2 by binding to its catalytic site. The ability of TIMP-2 to integrate MMP-2 is 7-9 fold higher than that of TIMP-1, so it is the most important factor imposed on the metabolism of type ІV collagen.
The serum TIMP-2 was found to be not related to the histological grade or stage. Therefore, unlike serum TIMP-1, the serum TIMP-2 level appears to be of little use for assessing liver fibrosis in patients with chronic liver disease.
It was found that the serum levels of TIMP-2 in patients with HCC did not differ significantly from those in patients with chronic hepatitis stage 4. It therefore seems that an elevated serum TIMP-2 level in patients with HCC may result from the underlying diseased liver rather than the HCC tissue, and that the serum TIMP-2 test is less useful for assessing HCC than the serum TIMP-1 test.