title: Vitamin D Deficiency Is Associated With Increased Risk of Non-alcoholic Steatohepatitis in Adults With Non-alcoholic Fatty Liver Disease: Possible Role for MAPK and NF-κB?
abstract: OBJECTIVE
  The objective of this study was to determine the relationship of serum vitamin D deficiency (VDD) to histologic features of non-alcoholic fatty liver disease (NAFLD), and associated demographic, clinical, laboratory, and transcriptomic data in the well-characterized Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN) cohort.
  
  
  METHODS
  Serum vitamin D 25(OH)D (VD) was quantified by liquid chromatography-tandem mass spectrometry in 190 adults (>18 years) with biopsy-proven NAFLD. Subjects were categorized according to their level of VD as either sufficient (>30 ng/ml), insufficient (≥20≤30 ng/ml), or deficient (VDD; <20 ng/ml). Multivariable logistic regression was used to investigate the association of VDD and the presence of definite NASH and individual histological features of NAFLD after adjusting for age, sex, race, body mass index, alanine aminotransferase, and diabetes status. Hepatic transcriptomic data was compared between VDD and non-VDD subjects.
  
  
  RESULTS
  VDD was present in 55% of subjects and was independently associated with definitive NASH (odds ratio (OR) 3.15, 95% confidence interval (CI), 1.62-6.15, P=0.001), increased lobular inflammation (OR=1.98, 95% CI, 1.08-3.61, P=0.026), more ballooning (OR=2.38, 95% CI, 1.32-4.30, P=0.004), and the presence of fibrosis (OR=2.32, 95% CI, 1.13-4.77, P=0.022). There was a significant inverse relationship between lower levels of serum resistin and increased VD level category (P=0.013). The KRT10, SEMA3B, SNORD3C, ARSD, and IGKV4-1 genes were differentially expressed (false discovery rate <0.05) between VDD and non-VDD subjects. Gene ontology and pathway analysis suggest activation of the mitogen-activated protein kinase and nuclear factor-κB pathways in VDD NAFLD subjects.
  
  
  CONCLUSIONS
  VDD is prevalent among US adult NAFLD patients and is independently associated with a definitive diagnosis of NASH and increased histological severity. Novel associations in proinflammatory pathways were identified, which suggest the mechanism for VDD in the pathogenesis of NASH and support dietary and/or lifestyle modifications to increase vitamin D levels in these patients.
authors.affiliation: Benaroya Research Institute at Virginia Mason Medical Center, Seattle, Washington, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Nelson
authors.affiliation: Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Roth
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, Baltimore, Maryland, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Wilson
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, Baltimore, Maryland, USA.
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Yates
authors.affiliation: Department of Physiological Nursing, University of California at San Francisco, San Francisco, California, USA.|Institute for Human Genetics, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Aouizerat
authors.affiliation: Liver Care Network, Swedish Medical Center, Seattle, Washington, USA.
authors.forename: Vicki
authors.initials: V
authors.lastname: Morgan-Stevenson
authors.affiliation: Benaroya Research Institute at Virginia Mason Medical Center, Seattle, Washington, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Whalen
authors.affiliation: Departments of Laboratory Medicine and Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hoofnagle
authors.affiliation: Benaroya Research Institute at Virginia Mason Medical Center, Seattle, Washington, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mason
authors.affiliation: Benaroya Research Institute at Virginia Mason Medical Center, Seattle, Washington, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Gersuk
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.affiliation: Benaroya Research Institute at Virginia Mason Medical Center, Seattle, Washington, USA.|Liver Care Network, Swedish Medical Center, Seattle, Washington, USA.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002853:Chromatography, Liquid; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism*; D012307:Risk Factors; D013472:Sunlight; D053719:Tandem Mass Spectrometry; D014808:Vitamin D Deficiency / Q000097:blood / Q000150:complications* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D016328:NF-kappa B