Best Practices in Liver Biopsy Histologic Assessment for Nonalcoholic Steatohepatitis Clinical Trials: Expert Opinion

Abstract

Background. In most clinical trials focusing on precirrhotic nonalcoholic steatohepatitis (NASH), a liver biopsy is required for confirmation of diagnosis, staging fibrosis, and grading steatohepatitis activity. Reliance on the biopsy, both as a requisite for study entry, as well as for a primary endpoint in clinical trials, poses several challenges that need to be overcome: patient reluctance to undergo the procedure; potential sampling error; concern regarding the handling, processing and shipping of the biopsy of the biopsy material to the central reader(s); and the degree of pathologists’ intra- and interobserver variability in biopsy interpretation. Aims. To provide recommendations for improving the liver biopsy process in order to maximize the accuracy of its histological interpretation in NASH clinical trials. Methods and Results. These recommendations were created by an expert panel of participants from the United States and European Union who met multiple times and reached alignment through review of available data and their individual clinical experiences. The recommendations include the methodology for biopsy procedure, central lab and pathology processing of the specimen, and recommendations to minimize the intra- and intersubject variability. Finally, we are discussing digital pathology technology and machine learning applications as important additions to enhance liver biopsy interpretation.Conclusions. Liver biopsy poses multiple challenges in clinical trials in NASH, and there is a need to standardize the processes to maximize accuracy and minimize variability. Many questions remained unanswered due to limited available data. New evolving modalities may help in the future, but generation of robust data is warranted.

Cardiac and Liver Fibrosis Assessed by Multiparametric MRI in Patients with Fontan Circulation

“…T1 and ECV may be less sensitive to hepatic flow changes, compared to MRE; however, it is still unclear whether liver native T1 mapping and ECV can help to differentiate between these conditions [30]. Liver biopsy remains the gold standard for diagnosis of liver fibrosis in many situations [41][42][43]. However, this technique is invasive and may be affected by sampling variability.…”

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“…Achieving the surrogate biopsy-based endpoints adopted by regulatory bodies for NASH clinical trials has been exceedingly difficult, owing to the slow rate at which NASH progresses and regresses 35 ; consequently, no NASH therapeutic has been approved. To address this challenge, several measurement systems that detect subordinal levels of histologic change have been proposed 36 . We previously demonstrated the utility of AI-based continuous measures of fibrosis for detecting subtle, yet statistically significant changes in fibrosis in response to treatment 5,34 .…”

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“…Biopsy interpretation can be limited by technical quality and intra-and inter-observer variability in the grading of histopathological features is well-documented in other liver diseases. [34][35][36] Also, evaluation of a continuous process (e.g. hepatocyte load or degree of inflammation) using a categorical instrument can lead to inconsistent scoring between pathologists, or for repeat assessments when scoring findings near the category breakpoints.…”

“…Development of categorical scoring systems for AATLD may be useful for characterising disease stage and progression over time but would carry the same limitations as seen with biopsy for other liver diseases. Biopsy interpretation can be limited by technical quality and intra‐ and inter‐observer variability in the grading of histopathological features is well‐documented in other liver diseases 34–36 . Also, evaluation of a continuous process (e.g.…”