Significant gene expression differences in histologically "Normal" liver biopsies: Implications for control tissue

Hepatology. 2008 Sep;48(3):953-62. doi: 10.1002/hep.22411.


Gene expression technologies allow the analysis of gene networks whose expression is associated with specific pathological conditions compared with normal tissue. We hypothesized that histologically normal tissue obtained in different ways (percutaneous or surgical liver biopsies), usually used as normal controls in gene expression studies, could have different gene expression patterns. Group A comprised percutaneous liver biopsies in 14 patients with mildly elevated alanine aminotransferase in whom all causes of liver disease had been ruled out. Group B comprised 14 surgical liver biopsies of nontumoral livers. All 28 specimens were histologically normal. Real-time quantitative reverse-transcription polymerase chain reaction were used to compare the messenger RNA expression of 240 selected genes in these two groups. Expression of 26 of the 240 genes was significantly different between groups A and B; 23 genes were up-regulated in group A, while three were down-regulated in group B. The most notable changes occurred in the inflammatory response family genes. Eight genes discriminated perfectly between groups A and B: seven up-regulated genes (PAI1, THBS1, IL8, PTGS2, CXCR4, JUN, and FOS), and one down-regulated gene (IHH). In chronic hepatitis C liver samples, a lower or higher expression of a IL8 was found depending on whether the controls were obtained percutaneously or surgically.

Conclusion: Our study demonstrates that histologically normal liver tissue obtained in two different ways (percutaneous or surgical) has different gene expression patterns emphasizing the importance of an adequate selection of histologically normal controls to prevent discordant results in gene expression studies.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy / methods*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Gene Expression Profiling*
  • Hepatitis C, Chronic / metabolism
  • Hepatitis C, Chronic / pathology
  • Humans
  • Interleukin-18 / genetics
  • Interleukin-18 / metabolism
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Liver / metabolism*
  • Liver / pathology*
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism
  • Reproducibility of Results
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism


  • CXCR4 protein, human
  • Interleukin-18
  • Interleukin-8
  • Plasminogen Activator Inhibitor 1
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Receptors, CXCR4
  • SERPINE1 protein, human
  • Thrombospondin 1
  • Cyclooxygenase 2