title: CD14 upregulation as a distinct feature of non-alcoholic fatty liver disease after pancreatoduodenectomy.
abstract: OBJECTIVE
  To investigate the pathogenesis of non-alcoholic fatty liver disease (NAFLD) after pancreatoduodenectomy (PD).
  
  
  METHODS
  A cohort of 82 patients who underwent PD at Okayama University Hospital between 2003 and 2009 was enrolled and the clinicopathological features were compared between patients with and without NAFLD after PD. Computed tomography (CT) images were evaluated every 6 mo after PD for follow-up. Hepatic steatosis was diagnosed on CT when hepatic attenuation values were 40 Hounsfield units. Liver biopsy was performed for 4 of 30 patients with NAFLD after PD who consented to undergo biopsies. To compare NAFLD after PD with NAFLD associated with metabolic syndrome, liver samples were obtained from 10 patients with NAFLD associated with metabolic syndrome [fatty liver, n = 5; non-alcoholic steatohepatitis (NASH), n = 5] by percutaneous ultrasonography-guided liver biopsy. Double-fluorescence immunohistochemistry was applied to examine CD14 expression as a marker of lipopolysaccharide (LPS)-sensitized macrophage cells (Kupffer cells) in liver biopsy specimens.
  
  
  RESULTS
  The incidence of postoperative NAFLD was 36.6% (30/82). Univariate analysis identified cancer of the pancreatic head, sex, diameter of the main pancreatic duct, and dissection of the nerve plexus as factors associated with the development of NAFLD after PD. Those patients who developed NAFLD after PD demonstrated significantly decreased levels of serum albumin, total protein, cholesterol and triglycerides compared to patients without NAFLD after PD, but no glucose intolerance or insulin resistance. Liver biopsy was performed in four patients with NAFLD after PD. All four patients showed moderate-to-severe steatosis and NASH was diagnosed in two. Numbers of cells positive for CD68 (a marker of Kupffer cells) and CD14 (a marker of LPS-sensitized Kupffer cells) were counted in all biopsy specimens. The number of CD68+ cells in specimens of NAFLD after PD was significantly increased from that in specimens of NAFLD associated with metabolic syndrome specimens, which indicated the presence of significantly more Kupffer cells in NAFLD after PD than in NAFLD associated with metabolic syndrome. Similarly, more CD14+ cells, namely, LPS-sensitized Kupffer cells, were observed in NAFLD after PD than in NAFLD associated with metabolic syndrome. Regarding NASH, more CD68+ cells and CD14+ cells were observed in NASH after PD specimens than in NASH associated with metabolic syndrome. This showed that more Kupffer cells and more LPS-sensitized Kupffer cells were present in NASH after PD than in NASH associated with metabolic syndrome. These observations suggest that after PD, Kupffer cells and LPS-sensitized Kupffer cells were significantly upregulated, not only in NASH, but also in simple fatty liver.
  
  
  CONCLUSIONS
  NAFLD after PD is characterized by both malnutrition and the up-regulation of CD14 on Kupffer cells. Gut-derived endotoxin appears central to the development of NAFLD after PD.
authors.affiliation: Daisuke Satoh, Takahito Yagi, Takeshi Nagasaka, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Masashi Utsumi, Hiroshi Sadamori, Toshiyoshi Fujiwara, Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Satoh
authors.forename: Takahito
authors.initials: T
authors.lastname: Yagi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Susumu
authors.initials: S
authors.lastname: Shinoura
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Umeda
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Yoshida
authors.forename: Masashi
authors.initials: M
authors.lastname: Utsumi
authors.forename: Takehiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sadamori
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
keywords: CD14; Endotoxin; Kupffer cells; Non-alcoholic fatty liver disease; Pancreatoduodenectomy