Department of Molecular Oncology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Asahi, Matsumoto, Japan.
J Clin Gastroenterol. 2010 Jul;44(6):440-7. doi: 10.1097/MCG.0b013e3181bdefe2.
Reliable noninvasive biomarkers to assess the histologic activity of nonalcoholic fatty liver disease (NAFLD) have not been established. As the frequency of Mallory bodies is known to be closely associated with the disease severity, we hypothesized that serum levels of Mallory body-related proteins were correlated with NAFLD histologic activity and evaluated this possibility.
Serum levels of total and fragmented cytokeratin (CK) 18, heat shock protein (Hsp) 70, Hsp90alpha, ubiquitin+1, and p38alpha at the time of liver biopsy were measured in 118 NAFLD patients and their association with histologic findings and NAFLD histologic activity score (NAS) was investigated.
Serum levels of both forms of CK18 and Hsp90alpha were markedly higher in patients having nonalcoholic steatohepatitis (NASH) compared with non-NASH ones. Both forms of CK18 significantly correlated with degree of steatosis, lobular inflammation, and ballooning, and showed stronger positive correlations with NAS than serum aspartate and alanine aminotransferase (AST and ALT). Multiple regression analysis further revealed that fragmented CK18 and AST were effective predictors of NAS, with the former being the more definitive of the two (P<0.001 vs. 0.005). In 20 NAFLD patients who received a follow-up biopsy, changes in fragmented CK18 levels, but not AST or ALT levels, closely paralleled those in NAS.
These results establish the usefulness of fragmented CK18 measurement for assessing and monitoring the histologic activity of NAFLD.
目前尚未建立可靠的非侵入性生物标志物来评估非酒精性脂肪性肝病（NAFLD）的组织学活动。已知 Mallory 小体的频率与疾病严重程度密切相关，我们假设 Mallory 体相关蛋白的血清水平与 NAFLD 的组织学活动相关，并对此进行了评估。
在肝活检时测量了 118 例 NAFLD 患者的总和片段细胞角蛋白（CK）18、热休克蛋白（Hsp）70、Hsp90alpha、泛素+1 和 p38alpha 的血清水平，并研究了它们与组织学发现和 NAFLD 组织学活动评分（NAS）的相关性。
与非 NASH 患者相比，患有非酒精性脂肪性肝炎（NASH）的患者的 CK18 两种形式和 Hsp90alpha 的血清水平明显更高。CK18 的两种形式均与脂肪变性、小叶炎症和气球样变的程度显著相关，与 NAS 的相关性比血清天冬氨酸和丙氨酸氨基转移酶（AST 和 ALT）更强。多元回归分析进一步表明，片段化 CK18 和 AST 是 NAS 的有效预测因子，前者比后者更为明确（P<0.001 与 0.005）。在 20 例接受随访肝活检的 NAFLD 患者中，片段化 CK18 水平的变化与 NAS 的变化密切平行，而 AST 或 ALT 水平的变化则没有。
这些结果确立了片段化 CK18 测量在评估和监测 NAFLD 的组织学活动中的有用性。
