Decision making for liver biopsy in NASH, not so FAST?
Authors: Ian A Rowe
Journal: The Lancet. Gastroenterology & hepatology (2020)

Liver biopsy is crucial for selecting patients with non-alcoholic steatohepatitis (NASH) for inclusion in clinical trials and, by implication, for treatment after new drugs are licensed. These clinical trials aim to include those patients considered to be at greatest risk of disease progression and liver-related morbidity and mortality, factors that are defined by the presence and severity of liver fibrosis. Almost all drugs for NASH currently being assessed in clinical trials aim to treat the inflammatory activity associated with NASH, and therefore the population being considered for treatment are patients with active NASH (non-alcoholic fatty liver disease activity score ≥4) and significant fibrosis (stage ≥F2). Many patients screened for clinical trials undergo liver biopsy that does not show sufficient activity or fibrosis for inclusion. Under those circumstances, the patient could be considered to have undergone an unnecessary investigation that has not contributed positively to their care.1Rowe IA Too much medicine: overdiagnosis and overtreatment of non-alcoholic fatty liver disease.Lancet Gastroenterol Hepatol. 2018; 3: 66-72Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar Preventing unnecessary liver biopsy in patients with NASH is an important goal, both to reduce complications and increase the proportion of patients who enter trials or start treatments that aim to improve outcomes. Using a combination of a blood test-based parameter (alanine aminotransferase [AST]) and parameters measured by vibration-controlled transient elastography (FibroScan, Echosens), Philip Newsome and colleagues2Newsome PN Sasso M Deeks JJ et al.FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study.Lancet Gastroenterol Hepatol. 2020; (published online Feb 3)https://doi.org/10.1016/S2468-1253(19)30383-8Summary Full Text Full Text PDF PubMed Scopus (241) Google Scholar aim to fill this gap with the FibroScan-AST (FAST) score. Although the methods used in the derivation and validation of the FAST score are undoubtedly of high quality, questions remain as to what extent this score will inform practice and reduce liver biopsy in patients with NASH. The authors propose two cutoffs in the FAST score. The first is at a low probability to identify patients at very low risk of active NASH with fibrosis. This is of clear value in preventing unnecessary liver biopsy in low risk patients, however, for half of the patients identified in this group in the derivation cohort the additional information provided by the FAST score is questionable, as the liver stiffness values were 6·1 kPa or less. This is a value at which few clinicians would request liver biopsy to identify patients for consideration of trials or treatment where fibrosis stage F2 or higher was a requirement. The second cutoff proposed is at a high probability of NASH with fibrosis. At this cutoff, the yield of liver biopsy is high for NASH with fibrosis, although a quarter of the patients identified in the derivation cohort at this level had cirrhosis. The usefulness of biopsy in NASH cirrhosis remains limited while there is a question as to whether treatments for NASH will show efficacy in cirrhosis, after disappointing results in recent studies.3Harrison SA Abdelmalek MF Caldwell S et al.Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis.Gastroenterology. 2018; 155: 1140-1153Summary Full Text Full Text PDF PubMed Scopus (183) Google Scholar These cutoffs leave a substantial proportion of patients within a grey zone, familiar to clinicians managing liver disease, where liver biopsy has often found a place. The challenge of considering liver biopsy in this context is in balancing the risks of a biopsy that does not indicate the patient for treatment, against the risks of missing treatable disease. To reach a conclusion on the value of biopsy to the patient in this context requires a further crucial piece of information that is not currently available: the effectiveness of treatments for NASH in reducing liver-related morbidity and mortality. The efficacy reported for the surrogate endpoints in the phase 2 trials that have supported the developments of treatments for NASH suggests that the benefit in terms of reductions of liver-related morbidity and mortality might be limited.4Ratziu V Harrison SA Francque S et al.Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.Gastroenterology. 2016; 150: 1147-1159Summary Full Text Full Text PDF PubMed Scopus (686) Google Scholar, 5Neuschwander-Tetri BA Loomba R Sanyal AJ et al.Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; 385: 956-965Summary Full Text Full Text PDF PubMed Scopus (1526) Google Scholar, 6Loomba R Lawitz E Mantry PS et al.The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial.Hepatology. 2018; 67: 549-559Crossref PubMed Scopus (358) Google Scholar, 7Friedman SL Ratziu V Harrison SA et al.A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.Hepatology. 2018; 67: 1754-1767Crossref PubMed Scopus (436) Google Scholar, 8Harrison SA Rinella ME Abdelmalek MF et al.NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.Lancet. 2018; 391: 1174-1185Summary Full Text Full Text PDF PubMed Scopus (279) Google Scholar In the FLINT trial,5Neuschwander-Tetri BA Loomba R Sanyal AJ et al.Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; 385: 956-965Summary Full Text Full Text PDF PubMed Scopus (1526) Google Scholar for example, the absolute proportion of participants with improved fibrosis above that seen in the placebo arm was 16%. When this is considered in the context of a patient with F2 fibrosis, in whom the probability of liver-related morbidity within 10 years is less than 10%,9Hagstrom H Nasr P Ekstedt M et al.Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD.J Hepatol. 2017; 67: 1265-1273Summary Full Text Full Text PDF PubMed Scopus (516) Google Scholar the likelihood that the patient will benefit from treatment is very low within that timeframe. This type of information will need to be defined by fibrosis stage to help clinicians and patients reach decisions regarding liver biopsy within the FAST score grey zone. Identification of patients at the greatest risk of liver-related morbidity and mortality will be a critical step in treatment decision-making. As we begin to understand the nature and the magnitude of the benefits of treatment, the use of tools, including the FAST score, to identify these patients will need to be developed and refined. I report personal fees from AbbVie outside the submitted work. FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation studyThe FAST score provides an efficient way to non-invasively identify patients at risk of progressive NASH for clinical trials or treatments when they become available, and thereby reduce unnecessary liver biopsy in patients unlikely to have significant disease. Full-Text PDF Open Access