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Serum biomarkers: -AST/ALT ratio — Ratio is usually 0.8. If >1 may reflect cirrhosis. -AST to platelet ratio index (APRI) —APRI = AST level (/ULN) X100(Plt count (10/l))- excludes fibrosis in chronic HCV. -PGA index —Combines Prothrombin index, GGT and apolipoprotein A1 (PGA) 68% accuracy to detect cirrhosis in alcoholics. -FibroIndex — The FibroIndex (derived from the plt count, AST, and gamma globulin measurements) for fibrosis in HCV- being validated. -FIB-4 — The FIB-4 combines biochemical values (platelet count, ALT and AST) and age. Good accuracy for fibrosis in HCV. -Fibrometer — The fibrometer test involves a combination of the platelet count, prothrombin index, AST, alfa 2 macroglobulin, hyaluronate, blood urea nitrogen, and age. Good accuracy for fibrosis in HCV. -Fibrotest (=Fibrosure) — The test involves assessment of alpha 2 macroglobulin, alpha 2 globulin (haptoglobin), gamma globulin, apolipoprotein A1, gamma glutamyl transferase and total bilirubin.Results from each test are formulated to determine mild fibrosis (Metavir F 0 to 1), significant fibrosis (Metavir F2 to 4) or indeterminate stage. Sensitivity and specificity for detection of significant fibrosis (F2 or greater) are approximately 75 and 85 %, respectively. Fibrotest with fibroscan has better accuracy when they agree. ActiTest — ActiTest is a Fibrotest modification that incorporates ALT and reflects both liver fibrosis and necroinflammatory activity. Reliable alternative to liver bx in Hep C. Liver Stiffness Assessed via USS transducer, a vibration of low frequency (50Mhz) and amplitude is transmitted into the liver, inducing an elastic shear wave. The velocity of the USS wave correlates with tissue stiffness. -Estimates for diagnosis of significant fibrosis were influenced by the type of underlying liver disease. The most consistent findings are in patients with hepatitis C. It is best for hep C - For cirrhosis, se 87 %/spe 91% -For stages II-IV fibrosis, the se 70 %/ sp 84%. Procollagen C-proteinase Procollagen N-proteinase Procollagen type III amino-terminal peptide ( PIIINP) — Levels inc. in acute and chronic liver diseases. Correlate with ALT levels in active hepatitis and with serum bilirubin levels in cirrhosis. PIIINP levels reflect the histological stage of hepatic fibrosis in alcoholic liver disease, viral hepatitis, and PBC Reduction or normalization of PIIINP levels have been observed in those who abstain from alcohol and in treatment responsive autoimmune hepatitis Hepatic venous blood has higher levels of PIIINP than peripheral venous or arterial samples. Procollagen type 1 carboxy-terminal peptide (PICP) — Increased in cirrhosis. Not as accurate as type IV collagen/ PIIINP in detecting the presence of cirrhosis, quantifying disease severity or indicating the presence of associated alc. hep. Type I collagen inc. in all liver fibrosis-not correlated with inflamm - tory activity score. Type IV collagen found in basement membrane of blood and lymph vessels, of bile ducts, around nerve axons, and in the perisinusoidal spaces. Inc in chronic liver diseases. More sensitive than laminin, hyaluronic acid, and PIIINP in diagnos - ing fibrosis in patients with chronic hepatitis.
Markers associated with matrix deposition — Hyaluronic acid, is a glycosaminoglycan synthesized by hepatic stellate cells and degraded by the liver sinusoidal cells-component of ECM. HA is correlated with impaired function of the endothelial sinusoidal cells/ increased fibrogenesis. Chondrex is a chitinase family member- correlated with the activity of arthritis. Chondrex is involved in degradation of extracellular matrix. Chondrex is increased in alcoholic liver disease, esp alc.hep. Chondrex is correlated with liver fibrosis and [hyaluronic acid]. Markers associated with collagen deposition
Matrix degradation occurs done by matrix metalloproteinases (MMPs). Inhibited by tissue inhibitors of metalloproteinases (TIMPs). The three most important MMPs appear to be: Matrix metalloproteinase-2 — Secreted by activated hepatic stellate cells. Significantly increased by collagen type-I. COnflicting data on correlation with hep C fibrosis Matrix metalloproteinase-3 — Probably not useful Matrix metalloproteinase-9 — Secreted by activated Kupffer cells +/- hepatic stellate cell Increased in HCC but not chronic hepatitis or cirrhosis. TIMP-1 and 2 — In chronic HCV disease, serum TIMP-1 and TIMP-2 levels correlated with histological activity index and with fibrosis, respectively but not specific. Laminin — Laminin is non-collagenous glycoprotein synthesized by the hepatic stellate cells and deposited 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 and the pepsin-resistant fragment of laminin (laminin P1) are elevated in alcoholic and viral liver disease which may reflect an increase in perisinusoidal fibrosis. Serum levels of laminin correlate with the severity of fibrosis. It is a sensitive and specific marker of acute alcoholic hepatitis. Laminin appears to be superior to PIIINP but not as good as collagen type IV in predicting fibrotic stage in chronic viral hepatitis. Cytokines and chemokines assoc with hepatic fibrosis : Transforming growth factor beta — Stimulates extracellular matrix by hepatic stellate cells. Transforming growth factor alpha — Stimulate proliferation of normal + neoplastic hepatocytes. Platelet derived growth factor — Upregulated following liver injury. Markers Of Cirrhosis
Markers assoc With Matrix Degradation
Disadvantages Limited if ascites or obesity present Not reliable with acute viral hepatitis. Other factors also influence liver stiffness values (liver stiffness values are higher in men, BMI >30 kg/m(2) and metabolic syndrome)
ER and golgi modification Intracellular
procollagen
RER translation
extracellular
protease cleavage
assembly
collagen fibril
Extracel - lular matrix Basal lamina Hyaluonic acid Decorin
Nidogen
Collagen IV
Laminin
Fibronectin
Integrins
Periecan
