Abstract: Disclosed are biomarkers and methods for accurate non-invasive diagnosis or prognosis of liver fibrosis in subjects with non-alcoholic fatty liver disease (NAFLD). The biomarkers include circulating levels of thrombospondin 2 (TSP2) and can be measured at any time during the course of the disease. The methods include any one of non-invasive evaluation of circulating levels of TSP2 alone, or together with other molecular biomarkers, physiologic or radiographic biomarkers. The methods are highly sensitive and detect advanced liver fibrosis with a sensitivity of about or greater than 80%. The methods may use the circulating levels of TSP2 alone, or together with other molecular biomarkers, physiologic or radiographic biomarkers to accurately predict the risk of developing advanced liver fibrosis in a subject.