Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
Department of Molecular and Translational Medicine, University of Brescia, Italy.
Neuropediatrics. 2021 Dec;52(6):441-447. doi: 10.1055/s-0040-1722673. Epub 2021 Jan 14.
Aicardi-Goutières syndrome (AGS) is a monogenic type-I interferonopathy that results in neurologic injury. The systemic impact of sustained interferon activation is less well characterized. Liver inflammation is known to be associated with the neonatal form of AGS, but the incidence of AGS-related hepatitis across lifespan is unknown.We compared natural history data including liver enzyme levels with markers of inflammation, (liver-specific autoantibodies and interferon signaling gene expression[ISG] scores). Liver enzymes were classified as normal or elevated by the fold increase over the upper limit of normal (ULN). The highest increases were designated as hepatitis, defined as aspartate-aminotransferase or alanine-aminotransferase threefold ULN, or gamma-glutamyl transferase 2.5-fold ULN. A larger cohort was used to further characterize the longitudinal incidence of liver abnormalities and the association with age and genotype.Across the AGS cohort ( = 102), elevated liver enzymes were identified in 76 individuals (74.5%) with abnormalities at a level consistent with hepatitis in 29 individuals (28.4%). SAMHD1 mutations were less likely to be associated with hepatitis (log-rank test; = 0.011). Hepatitis was associated with early-onset disease and microcephaly (log-rank test; microcephaly = 0.0401, age onset = 0.0355). While most subjects ( = 20/33) were found to have liver-specific autoantibodies, there was no association between the presence of autoantibodies or ISG scores with hepatitis-level enzyme elevations.In conclusion, all genotypes of AGS are associated with transient elevations of liver enzymes and the presence of liver-associated autoantibodies. This adds to our growing understanding of the systemic pathology AGS.
Aicardi-Goutières 综合征 (AGS) 是一种单基因的 I 型干扰素病，可导致神经损伤。干扰素持续激活的系统影响尚未得到很好的描述。众所周知，肝脏炎症与 AGS 的新生儿形式有关，但一生中与 AGS 相关的肝炎的发病率尚不清楚。我们比较了包括肝酶水平在内的自然病史数据与炎症标志物（肝特异性自身抗体和干扰素信号基因表达[ISG]评分）。肝酶通过相对于正常上限（ULN）的倍数增加来分类为正常或升高。最高的增加被指定为肝炎，定义为天冬氨酸转氨酶或丙氨酸转氨酶三倍 ULN，或谷氨酰转移酶 2.5 倍 ULN。更大的队列用于进一步描述肝脏异常的纵向发生率以及与年龄和基因型的关联。在 AGS 队列（ = 102）中，76 名个体（74.5%）的肝酶升高，29 名个体（28.4%）的异常水平与肝炎一致。SAMHD1 突变不太可能与肝炎相关（对数秩检验； = 0.011）。肝炎与早发性疾病和小头畸形相关（对数秩检验；小头畸形 = 0.0401，发病年龄 = 0.0355）。虽然大多数受试者（ = 20/33）被发现具有肝特异性自身抗体，但自身抗体的存在或 ISG 评分与肝炎水平的酶升高之间没有关联。总之，AGS 的所有基因型都与肝酶的短暂升高和肝脏相关自身抗体的存在有关。这增加了我们对 AGS 系统性病理学的理解。
