Serum markers of hepatic fibrosis

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MARKERS ASSOCIATED WITH MATRIX DEPOSITION –Carboxy and amino terminal procollagen peptides are cleaved off the procollagen molecule extracellularly during the synthesis of collagen fibrils and are released into the serum where they can be measured. Tests are available for the detection of procollagen type I carboxy-terminal peptide (PICP) and procollagen type III amino-terminal peptide (PIIINP).

Serum levels of PIIINP reflect histological stage of hepatic fibrosis in alcoholic liver disease, viral hepatitis, and primary biliary cirrhosis .Reduction or normalization of PIIINP levels have been observed in those who abstain from alcohol and in those with autoimmune hepatitis who successfully responded to immunosuppressive therapy. Hepatic venous blood has higher levels of PIIINP than peripheral venous or arterial samples. However, no association has been demonstrated between levels of PIIINP and degree of portal hypertension. High pretreatment levels of PIIINP have been associated with a poor response to interferon therapy in HCV.

Treatment with penicillamine and steroids reduced serum PIINP, although both drugs are ineffective for the treatment of PBC.

Type I and IV collagens – Levels of type I collagen are increased in all types of liver fibrosis. Serum levels of type I collagen are increased in patients with chronic liver disease and correlate with fibrosis score but not with the activity score .Despite this correlation, there is no association with portal pressure. Type IV collagen was more sensitive than laminin, hyaluronic acid, and PIIINP in diagnosing fibrosis in patients with chronic hepatitis. Serum type IV collagen levels greater than 115 ng/mL were 100 sensitive and 69 specific for the diagnosis of stage 3 to 4 fibrosis in hereditary hemochromatosis.

Laminin – Laminin is non-collagenous glycoprotein synthesized by the hepatic stellate cells and deposited in the basement membrane of the liver. In chronic liver injury, basement membrane components, particularly laminin, are increasingly deposited around the vessels, in the perisinusoidal spaces, and in the portal tracts. Serum levels of laminin correlates with severity of fibrosis and hepatitis, Child"s Pugh score, hepatic vein portal gradient, and complications of liver cirrhosis. Laminin appears to be superior to PIIINP but not as good as collagen type IV in predicting fibrotic stage in chronic viral hepatitis.

 Hyaluronic acid-High levels of HA in patients with liver disease and particularly those with cirrhosis have been related to impaired function of the endothelial sinusoidal cells, and reflect increased fibrogenesis. Abstinence from alcohol is associated with reductions in HA levels.

The level of HA appears to be the most useful marker of hepatic fibrosis and an independent predictor of severe complications of cirrhosis in patients with hepatitis C. A reduction of HA levels has been observed in patients with HCV who had a biochemical response to interferon monotherapy .Increased levels were associated with worsening of fibrosis. HA performs better than PIIINP and type IV collagen in identifying patients with cirrhosis due to PBC or HCV.

MARKERS ASSOCIATED WITH MATRIX DEGRADATION – Matrix degradation occurs predominantly as a consequence of the action of a family of enzymes known as the matrix metalloproteinases (MMPs). The three most important MMPs appear to be: MMP-2(secreted by activated hepatic stellate cells) (gelatinase-A), MMP-3 (stromelysin) and MMP-9 (gelatinase-B). Plasma levels of MMP-9 (predominantly secreted by activated Kupffer cells) are increased in hepatocellular carcinoma but not those with chronic hepatitis or cirrhosis when compared with normal controls.

Transforming growth factor beta – (TGF beta) is the dominant stimulus for the production of extracellular matrix by hepatic stellate cells.

Transforming growth factor alpha – Transforming growth factor alpha (TGF alpha) is a potent stimulant of mitosis of normal and neoplastic hepatocytes.

SUMMARY – none of these markers is liver specific.