利福平治疗减少新生仔猪肠外营养相关肝病

　　利福平短期治疗可减少肠外营养相关肝病（PNALD）所致胆汁淤积。贝勒医学院、美国农业部农业研究局儿童营养研究中心通过对幼猪PNALD模型进行研究，分别给予14天静脉注射利福平600mg/kg/d或生理盐水，发现利福平能显著降低血清直接胆红素和胆汁酸水平，减少胆汁淤积，这些作用依赖于核激素受体孕固烷（孕甾烷）X受体（PXR）及其靶基因的激活。

JPEN J Parenter Enteral Nutr. 2016;40(4):137-138.

Rifampicin Treatment Reduces Parenteral Nutrition-Associated Liver Disease in Neonatal Piglets.

Gregory J. Guthri; Barbara Stoll; Douglas Burrin.

USDA ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.

Purpose: Preterm infants with complications due to gastrointestinal immaturity can receive parenteral nutrition (PN) for periods greater than 2 weeks. These infants are at risk for a progressive increase in cholestatic liver disease marked by elevated serum bilirubin and bile acid levels and, in severe cases, steatosis and liver damage (PNALD). The elevated levels of bile acids in the liver due to cholestasis can precipitate this liver injury. Modalities to minimize bile acids in the liver may be beneficial for preventing liver damage. Treatment with the antibiotic rifampicin has been used in adults to treat cholestatic pruritus. Treatment with rifampicin has been shown to increase clearance of bile acids through activation of the nuclear hormone receptor pregnane x receptor (PXR). PXR target genes are enzymes involved in phase I and phase II drug detoxification, which lead to increased 6-alpha hydroxylation of bile acids and their subsequent glucuronidation, increasing overall hydrophilicity and clearance. Our aim was to test whether rifampicin treatment can suppress the development of PNALD in neonatal PN-fed piglets

Methods: Newborn pigs (4 days old) were implanted with jugular catheters and received PN for 14 days. Pigs received daily PN consisting of 240 mL/kg of fluid, 240 kcal/kg, 25 g/kg of carbohydrate, 14 g/kg of protein, and 10 g/kg of lipid; the parental lipid used was Intralipid. Pigs (n = 8/group) were infused intravenously with either saline (IL) or 600 mg/kg of Rifadin IV (RIF), each day for 14 days.

Results: Treatment with RIF led to a 3-fold increase in the PXR target phase I enzyme Cyp3a29 gene expression compared with IL. RIF increased protein but not mRNA expression of the phase II glucuronidation gene Ugt1a6. Pigs in the IL vs RIF group had higher levels of serum direct bilirubin (2.62 ± 0.33 vs 1.33 ± 0.23 mg/dL) and total bile acids (34.05 ± 6.69 vs 17.06 ± 2.50 μM). However, the liver and gall bladder bile acid pool did not differ between groups. RIF treatment did not adversely affect the liver, as liver weight was significantly lower in the RIF group compared with the IL group (65.99 ± 3.70 vs 55.02 ± 2.21 g/kg). A marker of liver injury, serum ALT levels were not different between IL (15.75 ± 1.92 U/L) and RIF (14.75 ± 1.53 U/L) groups and within the normal range.

Conclusions: Treatment with rifampicin was effective in suppressing serum direct bilirubin and bile acid levels. The clearance of bile acids did not appear to occur via increased biliary secretion into the gall bladder but likely through increased clearance in the urine. Rifampicin did not appear to be hepatotoxic to neonatal pigs at the dosage level used. We conclude that short-term rifampicin treatment can reduce cholestasis associated with PNALD.

Financial support: USDA Agricultural Research Service under Cooperative Agreement Number 58-6250-6-001.