Hepatocellular carcinoma (HCC) accounts for 80% to 90% of primary liver cancer and it is a major health problem worldwide, ranking the fifth most common cancer in the world. In the present study we aimed to explore new or highly pertinent rapid and sensitive markers for early diagnosis of hepatocellular malignant changes. Two groups of rats were used in this study, one served as control, the second as trichloroacetic acid (TCA) challenged group (0.5 g/kg/d for 5 days, sacrificed after 4 weeks). The results showed that TCA group had a significant increase in blood alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase ( ALP), and acetyl CoA synthase (ACAS) activities, total bilirubin, triglycerides, total glycosaminoglycans (TGAGs), parallel with alpha-fetoprotein (AFP). On the other hand, it induced a significant reduction in serum total lipoprotein lipase (TLPL) activity. The histopathological investigations of hepatic tissue confirmed these neoplastic changes induced by TCA. The three parameters (TGAGs level, TLPL and ACAS activities) can be added as new markers for early diagnosis of hepatocellular carcinoma and elevation of the sensitivity and specificity of AFP.