Features of liver tissue remodeling in intestinal failure during and after weaning off parenteral nutrition

Abstract

Background. Intestinal failure is associated frequently with liver injury, which persists after weaning off parenteral nutrition. We compared features of liver remodeling in intestinal failure during and after weaning off parenteral nutrition. Methods. Liver biopsies and serum samples were obtained from 25 intestinal failure patients at a median age of 9.7 years (interquartile range: 4.6-18) and from age-matched control patients. Seven patients had been receiving parenteral nutrition for 53 months (22-160), and 18 patients had been weaned off parenteral nutrition 6.3 years (2.4-17) earlier, after having received parenteral nutrition for 10 months (3.3-34). Expression of alpha-smooth muscle actin, collagen 1, proinflammatory cytokines, growth factors, and matrix metalloproteinases (MMPs) was measured.Results. Significant increases in immunohistochemical expression of alpha-smooth muscle actin and collagen 1 were observed predominantly in portal areas and were similar to increases seen in patients currently receiving parenteral nutrition and in patients weaned off parenteral nutrition. Gene and protein expressions of alpha-smooth muscle actin and collagen were interrelated. Gene expression of ACTA2, encoding alpha-smooth muscle actin, was increased only in patients who were receiving parenteral nutrition currently. Comparable upregulation of interleukin-1 (a and ß), epidermal growth factor, integrin-ß6, and MMP9 gene expression was observed in both patient groups, irrespective of whether they were receiving parenteral nutrition currently. Liver expression and serum levels of TIMP1 and MMP7 were increased only in the patients on parenteral nutrition currently but were not increased after weaning off parenteral nutrition. Conclusion. Intestinal failure is characterized by abnormal activation of hepatic myofibroblast and accumulation of collagen both during and after weaning off parenteral nutrition. Persistent transcriptional upregulation of proinflammatory and fibrogenic cytokines after weaning off parenteral nutrition suggests that factors other than parenteral nutrition may contribute to intestinal failureassociated liver disease. (Surgery 2016;160:632-42.)

New Insights Into Intestinal Failure–Associated Liver Disease in Children

“…This phase is characterized by increased liver immunohistochemical staining for smooth muscle actin, a marker of hepatic stellate cells, and increased collagen gene expression with accompanying up‐regulation of proinflammatory and profibrotic cytokines and growth factors (IL‐1α, IL‐1β, EGF, adhesion molecule integrin‐β6, and MMP9) in the liver. ( 26,27,30 ) This transcriptional profile suggests that altered intestinal barrier function and microbial dysbiosis that persist even after PN discontinuation may be the primary drivers of persistent HF (original magnification: panel A, H&E ×4; panel B, H&E ×10; panel C, H&E ×4; panel D, trichrome ×4). Abbreviations: Coll1 , collagen 1; EGF, epithelial growth factor; H&E, hematoxylin and eosin; MMP9, matrix metalloproteinase 9; α‐SMA, alpha‐smooth muscle actin; TNFα, tumor necrosis factor alpha.…”

“…( 64 ) IL‐1β engages hepatocyte IL1 receptors and, through NFκB signaling, down‐regulates LXR and canalicular ABCG5/G8, which promotes hepatocyte accumulation of intravenously infused phytosterols. ( 27,30,31 ) Reduced ileal enterocyte production of FGF19, attributable to ileal resection or disease, leads to less engagement of FGFR4 receptor on hepatocytes and releases CYP7A1 to catalyze synthesis of more potentially hepatotoxic bile acids. ( 36 ) The combined effect of high levels of retained stigmasterol and macrophage‐derived IL‐1β/NFκB signaling in the hepatocyte down‐regulates FXR, BSEP, and MRP2 and leads to bile acid retention and cholestatic injury.…”

“…Moreover, subsequent cytokine (primarily interleukin [IL]‐1β) production and secretion by activated hepatic macrophages engaged hepatocyte IL‐1 receptors and, through nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB) signaling, down‐regulated canalicular ABCG5/G8 , which promoted hepatocyte accumulation of intravenously infused phytosterols. The combined effect of high levels of stigmasterol and macrophage‐derived IL‐1β/NFκB signaling in the hepatocyte down‐regulated FXR, BSEP, and MRP2 and led to bile acid retention and cholestatic injury ( 27,30 ) (Fig. 3).…”

Pediatric Intestinal Failure: The Key Outcomes for the First 100 Patients Treated in a National Tertiary Referral Center During 1984–2017

“…Intestinal insufficiency is a term that describes the special need population of former patients with IF having reached full enteral nutrition (EN) by intestinal adaptation and compensative increase in enteral intake, with or without the help of pharmacological agents . Patients with intestinal insufficiency still experience significant gastrointestinal symptoms and may be at risk for malnutrition and dehydration, and as our group has shown, renal impairment and liver injury as well …”

“…13,14 Patients with intestinal insufficiency still experience significant gastrointestinal symptoms and may be at risk for malnutrition and dehydration, and as our group has shown, renal impairment and liver injury as well. 15,16 The non-SBS causes for pediatric IF include primary intestinal motility disorders (PIMDs) and various congenital intestinopathies. The likelihood of weaning off PN remains lower in these patient groups, necessitating expert longterm care to ensure adequate nutrition, while minimizing liver derangements and central venous catheter (CVC)associated hazards.…”