title: Liver histology during Mipomersen therapy for severe hypercholesterolemia.
abstract: BACKGROUND
  Mipomersen is an antisense oligonucleotide that inhibits apolipoprotein B synthesis and lowers plasma low-density lipoprotein cholesterol even in the absence of low-density lipoprotein receptor function, presumably from inhibition of hepatic production of triglyceride-rich very low-density lipoprotein particles. By virtue of this mechanism, mipomersen therapy commonly results in the development of hepatic steatosis. Because this is frequently accompanied by alanine aminotransferase elevations, concern has arisen that mipomersen could promote the development of steatohepatitis, which could in turn lead to fibrosis and cirrhosis over time.
  
  
  OBJECTIVE
  The objective of this study was to assess the liver biopsy findings in patients treated with mipomersen.
  
  
  METHODS
  We describe 7 patients who underwent liver biopsy during the mipomersen clinical development programs. Liver biopsies were reviewed by a single, blinded pathologist.
  
  
  RESULTS
  The histopathological features were characterized by simple steatosis, without significant inflammation or fibrosis.
  
  
  CONCLUSIONS
  These findings suggest that hepatic steatosis resulting from mipomersen is distinct from nonalcoholic steatohepatitis.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Nikroo
authors.initials: N
authors.lastname: Hashemi
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Odze
authors.affiliation: Genzyme Corporation, Cambridge, MA, USA; Department of Medicine, Division of Cardiology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Mary P
authors.initials: MP
authors.lastname: McGowan
authors.affiliation: Heart institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil.
authors.forename: Raul D
authors.initials: RD
authors.lastname: Santos
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik S G
authors.initials: ESG
authors.lastname: Stroes
authors.affiliation: Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: dcohen@partners.org.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
mesh_terms: D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D008078:Cholesterol, LDL / Q000097:blood; D003937:Diagnosis, Differential; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000175:diagnosis* / Q000209:etiology; D005260:Female; D005355:Fibrosis; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000473:pathology*; D009841:Oligonucleotides / Q000009:adverse effects / Q000627:therapeutic use*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D005227:Fatty Acids; D009841:Oligonucleotides; D014280:Triglycerides; C524142:mipomersen
keywords: Antisense oligonucleotide; Apolipoprotein B; Cholesterol; Fibrosis; Inflammation; LDL; Liver; Nonalcoholic fatty liver disease; Steatohepatitis; Triglycerides; VLDL