This prospective, single-center study evaluates and compares the tissue sample quality and patient comfort of different liver biopsy methods. While traditional percutaneous liver biopsy passes a needle through the abdominal wall into the liver, endoscopic ultrasound-guided liver biopsy (EUS-LB) offers an internal alternative performed via the stomach under sedation. However, the optimal EUS needle size and tip design remain unclear. Therefore, this trial directly compares the diagnostic tissue yield and patient-reported pain across four contemporary EUS needle strategies and the traditional percutaneous approach. The study utilizes a sequential-period cluster-randomized design, enrolling consecutive adult patients who require a clinically indicated, untargeted liver biopsy over five predefined, sequential eight-week periods. Each eight-week block serves as a cluster, during which all enrolled patients receive the specific biopsy needle assigned to that period. The trial begins with the standard percutaneous 18G TruCut needle cluster. To minimize bias, the sequence of the subsequent four EUS-guided needle clusters-consisting of 19G FNA, 19G FNB, 22G FNA, and 22G FNB needles-is determined beforehand using a computer-generated random sequence. All procedures are performed by the same clinical team using highly standardized techniques to compare total specimen length, complete portal tracts, and procedure-associated pain across all groups.

Inclusion Criteria:

• clinical indication for non-targeted liver biopsy
• written informed consent

Exclusion Criteria:

• ascites
• severe coagulopathy (INR >2.0 or platelet count <50 × 10³/µl)
• contraindications to endoscopy or sedation
• anatomical conditions precluding safe liver biopsy
• pregnancy

All consecutive adult patients undergoing clinically indicated untargeted liver biopsy during the study period at our tertiary liver center.