Pilot trials of oral betaine in participants with non-alcoholic fatty liver disease and elevated alanine aminotransferase

Background/Aim: Betaine, 20 grams/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. Methods: We performed three 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 g or 8 g daily for 12 weeks. In the second trial 10 participants received 1 g/d for 24 weeks while 16 participants received 2 g/d for 24 weeks in the third trial. Primary outcome was percent decline in 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. Results: At baseline, more than 75% of participants had NASH when tested by MASEF score. ALT, AST, cytokeratin 18, pro-C3, and MASEF score decreased significantly among participants receiving 8 g, 4 g, 2 g, but not 1 g. High density lipoprotein increased in the 4 g and 2 g cohorts; low density lipoprotein did not change. Approximately 35% reported mild, transient gastrointestinal symptoms. Conclusion: Betaine 8 g/d, 4 g/d, and 2 g/d for 12-24 weeks significantly reduced ALT and other serologic markers of liver injury among participants with clinically defined MASLD and an elevated ALT.