Pilot trials of oral betaine in participants with metabolic dysfunction-associated steatotic liver disease and elevated alanine aminotransferase
Andrew Lim, Sabrina Cruz, Aliya Asghar Uddin, Olga Malysheva, Marie A. Caudill, Cristina Alonso, Alejandro Montilla, M.A. Karsdal, Diana Julie Leeming, Alejandro E. Mayorca‐Guiliani, Frederik Høbjerg Svejsø, Craig J. McClain, Timothy R. Morgan
Abstract
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.