A. Park1, D. Alligood1, X. Liu2, K. Swanson1, C. Shi1, D. Alvarado1, J. Guo1, N.O. Davidson3, D.C. Rubin3, B.W. Warner1 1Washington University, Pediatric Surgery, St. Louis, MO, USA 2Washington University, Pathology, St. Louis, MO, USA 3Washington University, Gastroenterology, St. Louis, MO, USA
Introduction:
Short gut syndrome (SGS) results from extensive small bowel resection (SBR) during the treatment of many gastrointestinal conditions and associated with intestinal failure associated liver disease (IFALD). The development of IFALD has been linked to cellular stress as well as specific fat species found in parenteral nutrition (PN). Our laboratory has previously characterized a murine SBR model of PN-independent IFALD. The purpose of this study is to characterize the timing and severity of liver injury using standardized scoring criteria that develops after massive SBR in this model.
Methods:
Eight week old male and female C57BL/6J mice underwent sham operation (transection of the bowel and reanastomosis without resection; n=6) or 75% proximal SBR (n=6) in separate cohorts and orally fed a standard liquid diet. Mice were sacrificed and livers were harvested at 2, 5, 10, and 26 weeks. Liver injury was scored by a blinded pathologist using Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) criteria.
Results:
SBR mice demonstrated chronic liver injury with persistent serum transaminitis (Figure 1a) as well as increased expression of oxidative and endoplasmic reticular (ER) stress marker genes NAD(P)H quinone dehydrogenase and DNA damage inducible transcript 3 by q-RT-PCR (Nqo1 and Ddit3; Figure 1b). Over time, increased expression of fibrosis markers collagen and smooth muscle actin (Col1a1 and Acta2; Figure 1b) was observed. By 26 weeks, all SBR livers had evidence for cirrhosis and nodular fibrosis upon gross examination (Figure 1c, nodules indicated with arrows) and by staining with Sirius Red (Figure 1d). When pathologically scored according to NASH CRN criteria, livers from resected mice had high scores (Figure 1e).
Conclusion:
Massive SBR is associated with significant liver inflammation as soon as 2 weeks after SBR which evolves into progressive steatohepatitis and eventual end stage cirrhosis. These findings validate a relatively rapid progression of liver disease after SBR in a PN-independent model of IFALD. This study validates the extra-hepatic insult and injury, steatosis, and fibrosis paradigm associated with other models of liver failure.