Pilot trials of oral betaine in participants with metabolic dysfunction-associated steatotic liver disease and elevated alanine aminotransferase

BACKGROUND AND AIMS: Betaine, 20 g/day for 12 months, reduced liver injury in several trials in non-alcoholic steatohepatitis (NASH). Our aim was to determine the safety and efficacy of lower doses of betaine in clinically diagnosed metabolic dysfunction-associated steatotic liver disease (MASLD) and an elevated ALT. APPROACH AND RESULTS: We performed 3 pilot trials in participants with clinically diagnosed non-cirrhotic MASLD and ALT ≥50 U/L. In the first trial, 44 participants were randomized to 4 or 8 g daily for 12 weeks. In the second trial, 10 participants received 1 g/day for 24 weeks, while 16 participants received 2 g/day for 24 weeks in the third trial. The primary outcome was the percent decline in the abnormal component of ALT (ie, ALT >30 for males or >25 for females). Other outcomes included improvement in absolute ALT and AST, and other serologic tests of liver injury, including metabolomics-advanced steatohepatitis fibrosis (MASEF) score, cytokeratin 18, and pro-C3. Baseline and end-of-treatment data were compared with a paired t test. At baseline, more than 75% of participants had NASH when tested by the MASEF score. ALT, AST, cytokeratin 18, pro-C3, and MASEF score decreased significantly among participants receiving 8, 4​​​​​, and 2 g, but not 1 g. High-density lipoprotein increased in the 4 and 2 g cohorts; low-density lipoprotein did not change. Approximately 35% reported mild, transient gastrointestinal symptoms. CONCLUSIONS: Betaine 8, 4​​​​​​, and 2 g/day for 12-24 weeks significantly reduced ALT and other serologic markers of liver injury among participants with clinically defined MASLD and an elevated ALT.