Nonalcoholic steatohepatitis is associated with a state of betaine‐insufficiency

Background and Aims Nonalcoholic fatty liver disease ( NAFLD ) develops from a complex process, which includes changes in the liver methylome. Betaine plays a pivotal role in the regulation of methylogenesis. We performed a two‐stage case–control study, which included patients with biopsy‐proven NAFLD to explore circulating levels of betaine and its association with the histological spectrum. We also explored the association between a missense rs1805074, p.Ser646Pro variant in DMGDH (dimethylglycine dehydrogenase mitochondrial) and NAFLD severity (n=390). Results In the discovery phase (n=48), betaine levels were associated with the disease severity ( P =.0030), including liver inflammation (Spearman R:−0.51, P =.001), ballooning degeneration (R: −0.50, P =.01) and fibrosis (R: −0.54, P =.0008). Betaine levels were significantly decreased in nonalcoholic steatohepatitis ( NASH ) in comparison with nonalcoholic fatty liver ( NAFL ). Further replication (n=51) showed that betaine levels were associated with advanced NAFLD ( P =.0085), and patients with NASH had a 1.26‐fold decrease in betaine levels compared with those with NAFL . The rs1805074 was significantly associated with the disease severity ( P =.011). Conclusion NAFLD severity is associated with a state of betaine‐insufficiency.