高血糖素样肽-2改善肠外营养相关肝病胆汁淤积

　　背景：肠外营养相关肝病（PNALD）依然是新生儿肠衰竭发病率和死亡率居高不下的重要原因。虽然高血糖素样肽-2（GLP-2）正被进一步开发成药物，但GLP-2对PNALD的疗效尚不清楚。我们旨在研究给予GLP-2对PNALD幼猪模型肝功能改善的疗效。

　　方法：对幼猪（出生后2～6天）通过颈静脉置管肠外营养（PN）方式给予相同氮量和热卡。将幼猪分为2组：第1组（n=8）给予生理盐水，第2组（n=7）给予GLP-2（11nmol/kg/d）。17天后，对幼猪进行剖腹手术并测其胆汁流量。通过组织病理学和免疫过氧化物酶染色对肝脏标本进行分析。选取年龄匹配母猪喂养的幼猪作为对照（第3组，n=8）。

　　结果：与母猪喂养的对照组相比，接受PN的第1组和第2组均出现了胆汁淤积，表现为胆汁流量的降低和血清总胆红素的升高。然而，与第1组相比，第2组的胆汁流量较高（1.35比0.73μL/g；P=0.02），血清胆红素较低（38.0比78.5μmol/L；P=0.008）。同时第2组的血清肝损伤指标丙氨酸转氨酶（ALT）水平较低。组织病理学显示：第1组的肝脏标本肝细胞中存在明显色素沉着，而第2组标本减少。

　　结论：外源性给予GLP-2有利于改善胆汁淤积和肝损伤。本研究介绍了GLP-2改善长期PN相关性PNALD的新作用。

JPEN J Parenter Enteral Nutr. 2016;40(1):14-21.

Glucagon-Like Peptide 2 Improves Cholestasis in Parenteral Nutrition-Associated Liver Disease.

Lim DW, Wales PW, Josephson JK, Nation PN, Wizzard PR, Sergi CM, Field CJ, Sigalet DL, Turner JM.

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada; Department of Surgery, Hospital for Sick Children & University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Alberta, Canada; Department of Agricultural Food & Nutritional Science, University of Alberta, Edmonton, Alberta, Canada; Department of Surgery, University of Calgary, Calgary, Alberta, Canada.

BACKGROUND: Parenteral nutrition-associated liver disease (PNALD) remains a significant cause of morbidity and mortality in neonates with intestinal failure. Although glucagon-like peptide-2 (GLP-2) is being advanced as therapy, the effect of GLP-2 treatment on PNALD is unknown. We aim to investigate the effect of exogenous GLP-2 administration on hepatic function in a neonatal piglet model of PNALD.

METHODS: Neonatal piglets (aged 2-6 days) underwent jugular venous catheterization to receive isonitrogenous, isocaloric parenteral nutrition (PN). Piglets were allocated to 2 groups: group 1 (n = 8) received saline while group 2 (n = 7) received GLP-2 (at 11 nmol/kg/d). After 17 days, piglets underwent terminal laparotomy, and bile flow was measured. Liver specimens were analyzed histologically and with immunoperoxidase staining. Age-matched sow-reared control piglets (group 3, n = 8) were used for comparison.

RESULTS: Both groups 1 and 2 receiving PN developed cholestasis relative to sow-reared controls, as evidenced by a decrease in bile flow and increase in serum total bilirubin. However, group 2 had improved bile flow (1.35 vs 0.73 µL/g; P = .02) and diminished bilirubin (38.0 vs 78.5 µmol/L; P = .008) compared with group 1. Group 2 also had lower serum alanine aminotransferase levels, a marker of liver injury. Histologically, the liver specimens in group 1 had marked hepatocyte pigmentation, which was decreased in group 2 specimens.

CONCLUSIONS: The exogenous administration of GLP-2 is associated with the improvement of cholestasis and liver injury. This study introduces a novel role for GLP-2 in improving PNALD in the setting of prolonged PN duration.

KEYWORDS: cholestasis; glucagon-like peptide 2; intestinal failure; neonate; parenteral nutrition; parenteral nutrition associated liver disease

PMID: 25280755

DOI: 10.1177/0148607114551968