A clinical trial on the follow-up of nonalcoholic fatty liver disease: An evaluation of pathological endpoint

Liver biopsy is the“gold standard”for the diagnosis of nonalcoholic fatty liver disease (NAFLD) /nonalcoholic steatohepatitis (NASH) . Although liver biopsy has several limitations including invasiveness and errors in sampling and evaluation, in clinical trials on NAFLD/NASH follow-up and new drugs, liver histological evaluation is still a main and irreplaceable method for inclusion/exclusion diagnosis and assessment of primary endpoints in cohorts. It often takes 10-20 years for NASH to progress to liver cirrhosis, which is a surrogate endpoint in clinical trials for new drugs, and the NASH Clinical Research Network (NASH-CRN) system is recommended as the histological evaluation system in clinical trials for tracking NAFLD/NASH. The primary endpoint for NASH treatment is usually set as the reversal of NASH without progression of fibrosis; an alternative one is a reduction in NAS score by at least 2 points and a reduction in one or more histological parameters by at least 1 point, without progression of fibrosis, during the full-course treatment. Patients in phase 2 b and 3 clinical trials should be monitored for at least 12 months, and if the improvement of fibrosis is set as the main assessment index, they should be monitored for at least 1-2 years and should be followed up for more than 6 months after drug withdrawal. Histological evaluation is affected by various factors. In order to ensure the quality of such evaluation, the length of tissue for liver biopsy should be larger than 2 cm (containing more than 10 portal areas) . Staining and section preparation should be performed at the same time, and more than two experts specializing in liver pathology should perform single-or double-blinded review of liver biopsies to avoid evaluation bias.