Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing 100044, China.
Nutrients. 2022 Mar 14;14(6):1224. doi: 10.3390/nu14061224.
There is evidence that vitamin B12 and associated metabolite levels are changed in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, their association has been in dispute.
We included 8397 individuals without previous liver condition or excess alcohol intake from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. NAFLD was diagnosed with Fatty Liver Index (FLI) ≥ 60 or USFLI ≥ 30, and participants with advanced fibrosis risks were identified with elevated non-alcoholic fatty liver disease fibrosis score (NFS), fibrosis 4 index (FIB-4), or aspartate aminotransferase (AST)/platelet ratio index (APRI). Step-wide logistic regression adjusting for confounders was used to detect the association between NAFLD or advanced fibrosis with serum vitamin B12, folate, red blood cell folate (RBC folate), homocysteine (HCY), and methylmalonic acid (MMA).
The weighted prevalence of NAFLD was 44.2%. Compared with non-NAFLD participants, patients with NAFLD showed significantly increased RBC folate level and RBC counts, decreased serum vitamin B12 and folate, and similar HCY and MMA levels. NAFLD with advanced fibrosis risk had higher MMA and HCY, reduced serum vitamin B12, and similar serum folate and RBC folate levels than NAFLD with low fibrosis risk. Only RBC folate was independently associated with an increased risk of NAFLD (OR (95% CI): 2.24 (1.58, 3.18)). In all participants, MMA (OR: 1.41 (1.10, 1.80)) and HCY (OR: 2.76 (1.49, 5.11)) were independently associated with increased risk for advanced fibrosis. In participants with NAFLD, this independent association still existed (OR: 1.39 (1.04, 1.85) for MMA and 1.95 (1.09, 3.46) for HCY). In all participants, the area under the receiver operating characteristic curve (ROC AUC) on fibrosis was 0.6829 (0.6828, 0.6831) for MMA and 0.7319 (0.7318, 0.7320) for HCY; in participants with NAFLD, the corresponding ROC AUC was 0.6819 (0.6817, 0.6821) for MMA and 0.6926 (0.6925, 0.6928) for HCY.
Among vitamin B12-associated biomarkers, RBC folate was independently associated with elevated NAFLD risk, whereas MMA and HCY were associated with increased risk for advanced fibrosis in the total population and NAFLD participants. Our study highlighted the clinical diagnostic value of vitamin B12 metabolites and the possibility that vitamin B12 metabolism could be a therapeutic target for NASH. Further studies using recent perspective data with biopsy proven NASH could be conducted to validate our results.
有证据表明，非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）患者的维生素 B12 和相关代谢物水平发生改变；然而，其相关性仍存在争议。
我们纳入了来自 1999-2004 年国家健康和营养检查调查（NHANES）的 8397 名无既往肝脏疾病或过量饮酒史的个体。NAFLD 采用脂肪性肝病指数（FLI）≥60 或 USFLI≥30 进行诊断，通过非酒精性脂肪性肝病纤维化评分（NFS）、纤维化 4 指数（FIB-4）或天门冬氨酸氨基转移酶（AST）/血小板比值指数（APRI）升高识别出有进展性纤维化风险的患者。采用逐步全变量逻辑回归校正混杂因素，以检测 NAFLD 或进展性纤维化与血清维生素 B12、叶酸、红细胞叶酸（RBC 叶酸）、同型半胱氨酸（HCY）和甲基丙二酸（MMA）之间的关系。
加权的 NAFLD 患病率为 44.2%。与非 NAFLD 参与者相比，NAFLD 患者的 RBC 叶酸水平和红细胞计数显著升高，血清维生素 B12 和叶酸水平降低，HCY 和 MMA 水平相似。有进展性纤维化风险的 NAFLD 患者的 MMA 和 HCY 水平较高，血清维生素 B12 水平降低，血清叶酸和 RBC 叶酸水平与低纤维化风险的 NAFLD 患者相似。只有 RBC 叶酸与 NAFLD 风险增加独立相关（比值比（95%置信区间）：2.24（1.58，3.18））。在所有参与者中，MMA（比值比：1.41（1.10，1.80））和 HCY（比值比：2.76（1.49，5.11））与进展性纤维化风险增加独立相关。在 NAFLD 患者中，这种独立相关性仍然存在（MMA 的比值比：1.39（1.04，1.85），HCY 的比值比：1.95（1.09，3.46））。在所有参与者中，MMA 的曲线下面积（ROC AUC）为 0.6829（0.6828，0.6831），HCY 的 ROC AUC 为 0.7319（0.7318，0.7320）；在 NAFLD 患者中，MMA 的 ROC AUC 为 0.6819（0.6817，0.6821），HCY 的 ROC AUC 为 0.6926（0.6925，0.6928）。
在维生素 B12 相关生物标志物中，RBC 叶酸与 NAFLD 风险增加独立相关，而 MMA 和 HCY 与全人群和 NAFLD 患者的进展性纤维化风险增加相关。我们的研究强调了维生素 B12 代谢物的临床诊断价值，以及维生素 B12 代谢可能成为 NASH 的治疗靶点的可能性。使用最近的有活检证实的 NASH 的前瞻性数据进行进一步研究，可以验证我们的结果。
