Use of N-of-1 trials in liver diseases: A systematic review

BACKGROUNDChronic liver diseases are heterogeneous and include autoimmune, genetic, metabolic, cholestatic, vascular, and idiopathic etiologies.Rare or slowly progressive conditions may make conventional randomized controlled trials difficult to conduct.The N-of-1 trial design offers a rigorous alternative for evaluating individualized treatment effects. AIMTo map the extent, nature, and characteristics of N-of-1 trials in liver diseases and identify research gaps. METHODSWe followed the Joanna Briggs Institute methodology for scoping reviews and PRISMA extension for Scoping Reviews reporting standards, using the Population, Concept, and Context framework.The Population comprised patients with chronic liver disease, the Concept was the use of an N-of-1 trial design, and the Context included clinical or health care settings worldwide, without geographic restriction.We searched MEDLINE (via Ovid), EMBASE, Scopus, and the Cochrane Library from inception through March 17, 2026.Two reviewers independently screened records in Covidence, with disagreements resolved by consensus.Eligible sources were English-language publications explicitly using an N-of-1 design in patients with liver diseases.Data charting captured study design, population, interventions, outcomes, and statistical methods.According to Joanna Briggs Institute guidance, a formal risk-of-bias assessment was not required; however, an optional narrative appraisal was performed. RESULTS / 31Of 76 records identified, 2 empirical N-of-1 studies met the eligibility criteria.One evaluated oral thiamine in 3 patients with chronic hepatitis B and reported reduced aminotransferase levels and improved virological markers using t-tests.However, the pooled analysis of data from only 3 patients was statistically problematic and should not be considered strong evidence.The second study evaluated ursodeoxycholic acid in a patient with hepatic sarcoidosis over four crossover cycles and demonstrated improvement in cholestasis using a Wilcoxon test for paired data.The optional narrative appraisal found that both studies lacked randomization and blinding and did not use pre-specified protocols, raising concerns about internal validity.CONCLUSION No identified study used aggregated N-of-1 analyses, Bayesian methods, or frameworks for integrating N-of-1 evidence into clinical decision-making.N-of-1 trials remain markedly underused in hepatology despite the presence of rare, stable, chronic liver diseases for which traditional randomized controlled trials may be impractical.Broader adoption, supported by Bayesian analytical methods, electronic health record integration, and reporting aligned with the CONSORT extension specifically developed for N-of-1 trials, could advance personalized care and complement conventional trial designs in future hepatology research.