Department of Neonatology, San Antonio Military Medical Center, San Antonio, TX, United States of America.
Department of Pediatrics, Brooke Army Medical Center, San Antonio, TX, United States of America.
PLoS One. 2020 Mar 9;15(3):e0228985. doi: 10.1371/journal.pone.0228985. eCollection 2020.
Parenteral Nutrition (PN) Associated Liver Disease (PNALD) affects up to 60% of neonates; however, techniques for diagnosing and monitoring disease progression remain limited. The neonatal baboon model may provide a unique opportunity to identify serologic markers associated with this disease. The purpose of this study was to investigate if Hyaluronic Acid (HA), TIMP metallopeptidase inhibitor 1 (TIMP1), Amino-terminal Propeptide of Type-III Collagen (PIIINP) and Enhanced Liver Fibrosis (ELF) score associate with histological liver disease in neonatal baboons exposed to PN. Preterm baboons delivered via c-section at 67% gestation received PN for 14 days with or without Intralipid (PRT+IL, PRT-IL, respectively) or were sacrificed after birth (PRTCTR). Term baboons were sacrificed after birth (TERMCTR) or survived 14 days (TERM+14d). Serum HA, TIMP1, and PIIINP concentrations were measured by ELISA. A blinded pathologist assigned liver histological scores following necropsy. HA increased 9.1-fold, TIMP1 increased 2.2-fold, and ELF score increased 1.4-fold in PRT-IL compared to PRTCTR. ALT, AST, and GGT were within normal limits and did not vary between groups. A trend towards increased fibrosis was found in PRT-IL baboons. Microvesicular hepatocyte steatosis and Kupffer cell hypertrophy were elevated in PRT-IL vs PRTCTR. HA and TIMP1 were significantly elevated in preterm baboons with early histological findings of liver disease evidenced by hepatic steatosis, Kupffer cell hypertrophy and a trend towards fibrosis whereas traditional markers of liver disease remained normal. These novel markers could potentially be utilized for monitoring early hepatic injury in neonates.
肠外营养（PN）相关肝病（PNALD）影响高达 60%的新生儿；然而，诊断和监测疾病进展的技术仍然有限。新生狒狒模型可能为识别与这种疾病相关的血清标志物提供独特的机会。本研究的目的是研究透明质酸（HA）、金属蛋白酶抑制剂 1（TIMP1）、III 型胶原氨基端前肽（PIIINP）和增强型肝纤维化（ELF）评分是否与接受 PN 的新生狒狒的组织学肝脏疾病相关。通过剖宫产在 67%孕龄分娩的早产狒狒接受 PN14 天，分别用或不用 Intralipid（PRT+IL、PRT-IL），或在出生后处死（PRTCTR）。足月狒狒在出生后处死（TERMCTR）或存活 14 天（TERM+14d）。通过 ELISA 测量血清 HA、TIMP1 和 PIIINP 浓度。盲法病理学家在尸检后分配肝脏组织学评分。与 PRTCTR 相比，PRT-IL 中 HA 增加了 9.1 倍，TIMP1 增加了 2.2 倍，ELF 评分增加了 1.4 倍。ALT、AST 和 GGT 在正常范围内，各组之间无差异。在 PRT-IL 狒狒中发现纤维化有增加的趋势。与 PRTCTR 相比，PRT-IL 狒狒的微泡性肝细胞脂肪变性和枯否细胞肥大增加。HA 和 TIMP1 在有早期肝疾病组织学表现的早产狒狒中显著升高，表现为肝脂肪变性、枯否细胞肥大和纤维化趋势，而传统的肝病标志物仍正常。这些新的标志物可能可用于监测新生儿的早期肝损伤。
