Liver Center, Massachusetts General Hospital, Boston, Massachusetts.
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Inflamm Bowel Dis. 2018 Sep 15;24(10):2247-2257. doi: 10.1093/ibd/izy128.
Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized comorbidity in Crohn's disease (CD), but the mechanisms are poorly understood. Autophagy is a highly conserved process regulating innate immunity that contributes to CD susceptibility. Emerging data suggest that variants in the autophagy-governing IRGM gene may contribute to the accumulation of visceral adipose tissue (VAT) and hepatic fat. Our objective was to characterize the relationship between VAT, IRGM gene variants, and NAFLD risk in patients with CD.
We included all CD patients in the Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM) without history of alcohol abuse or liver disease. Hepatic fat was quantified by liver attenuation (LA) on computed tomography, with NAFLD defined by the validated liver:spleen (L:S) ratio. NAFLD severity was estimated by the FIB-4 Index and alanine aminotransferase (ALT). Using logistic regression modeling, we examined the relationship between VAT, autophagy gene variants, and NAFLD risk.
Among 462 patients, 52% had NAFLD. Increasing VAT quartile was associated with reduced LA (mean change, -7.43; 95% confidence interval [CI], -10.05 to -4.81; Ptrend < 0.0001). In the fully adjusted model, patients in the highest VAT quartile had a 2.2-fold increased NAFLD risk (95% CI, 1.21 to 4.14; Ptrend = 0.032) and a 4.2-fold increased risk of ALT>upper limit of normal (ULN) (95% CI, 1.19 to 14.76; Ptrend = 0.017). The relationship between VAT and NAFLD was modified by IRGM variants rs4958847 and rs13361189 (Pinteraction = 0.005 and Pinteraction < 0.001, respectively).
In a large CD cohort, VAT was directly associated with prevalent NAFLD, and this relationship was augmented by functionally annotated IRGM variants associated with impaired autophagy.
非酒精性脂肪性肝病（NAFLD）是克罗恩病（CD）日益被认识到的合并症，但发病机制尚不清楚。自噬是一种高度保守的调节先天免疫的过程，有助于 CD 的易感性。新出现的数据表明，自噬调控基因 IRGM 中的变异可能导致内脏脂肪组织（VAT）和肝脂肪的积累。我们的目的是描述 CD 患者中 VAT、IRGM 基因变异与 NAFLD 风险之间的关系。
我们纳入了马萨诸塞州总医院炎症性肠病研究前瞻性登记处（PRISM）中所有无酒精滥用或肝脏疾病史的 CD 患者。通过计算机断层扫描的肝衰减（LA）定量肝脂肪，通过验证的肝脾（L：S）比值定义 NAFLD。通过 FIB-4 指数和丙氨酸氨基转移酶（ALT）估计 NAFLD 严重程度。我们使用逻辑回归模型检查 VAT、自噬基因变异与 NAFLD 风险之间的关系。
在 462 例患者中，52%有 NAFLD。随着 VAT 四分位的增加，LA 降低（平均变化，-7.43；95%置信区间[CI]，-10.05 至-4.81；Ptrend <0.0001）。在完全调整的模型中，VAT 最高四分位的患者 NAFLD 风险增加 2.2 倍（95%CI，1.21 至 4.14；Ptrend =0.032），ALT>正常值上限（ULN）的风险增加 4.2 倍（95%CI，1.19 至 14.76；Ptrend =0.017）。VAT 与 NAFLD 之间的关系受 IRGM 变异 rs4958847 和 rs13361189 调节（P 交互=0.005 和 P 交互<0.001）。
在一个大型 CD 队列中，VAT 与普遍存在的 NAFLD 直接相关，这种关系被与受损自噬相关的功能注释的 IRGM 变体增强。
