Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease

Cynthia D. Guy, Ayako Suzuki, James L. Burchette, Elizabeth M. Brunt, Manal F. Abdelmalek, Diana Cardona, Shannon J. McCall, Aynur Ünalp, Patricia Belt, Linda D. Ferrell, Anna Mae Diehl

Research output: Contribution to journalArticle

Abstract

Nonalcoholic fatty liver disease is a global health dilemma. The gold standard for diagnosis is liver biopsy. Ballooned hepatocytes are histologic manifestations of hepatocellular injury and are characteristic of steatohepatitis, the more severe form of nonalcoholic fatty liver disease. Definitive histologic identification of ballooned hepatocytes on routine stains, however, can be difficult. Immunohistochemical evidence for loss of the normal hepatocytic keratin 8/18 can serve as an objective marker of ballooned hepatocytes. We sought to explore the utility of a keratin 8/18 plus ubiquitin double immunohistochemical stain for the histologic evaluation of adult nonalcoholic fatty liver disease. Double immunohistochemical staining for keratin 8/18 and ubiquitin was analyzed using 40 adult human nonalcoholic fatty liver disease core liver biopsies. Ballooned hepatocytes lack keratin 8/18 staining as previously shown by others, but normal-size hepatocytes with keratin loss are approximately 5 times greater in number than keratin-negative ballooned hepatocytes. Keratin-negative ballooned hepatocytes, normal-size hepatocytes with keratin loss, and ubiquitin deposits show a zonal distribution, are positively associated with each other, and are frequently found adjacent to or intermixed with fibrous matrix. All 3 lesions correlate with fibrosis stage and the hematoxylin and eosin diagnosis of steatohepatitis (all P <.05). Compared with hematoxylin and eosin staining, immunohistochemical staining improves the receiver operating characteristics curve for advanced fibrosis (0.77 versus 0.83, 0.89, and 0.89 for keratin-negative ballooned hepatocytes, normal-size hepatocytes with keratin loss, and ubiquitin, respectively) because immunohistochemistry is more sensitive and specific for fibrogenic hepatocellular injury than hematoxylin and eosin staining. Keratin 8/18 plus ubiquitin double immunohistochemical stain improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Thus, it may help differentiate nonalcoholic steatohepatitis from nonalcoholic fatty liver.

Original languageEnglish (US)
Pages (from-to)790-800
Number of pages11
JournalHuman pathology
Volume43
Issue number6
DOIs
StatePublished - Jun 1 2012

Keywords

  • Ballooned hepatocytes
  • Endoplasmic reticulum stress
  • Immunohistochemistry
  • Insulin resistance
  • Intermediate filaments
  • Nonalcoholic steatohepatitis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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  • Cite this

    Guy, C. D., Suzuki, A., Burchette, J. L., Brunt, E. M., Abdelmalek, M. F., Cardona, D., McCall, S. J., Ünalp, A., Belt, P., Ferrell, L. D., & Diehl, A. M. (2012). Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Human pathology, 43(6), 790-800. https://doi.org/10.1016/j.humpath.2011.07.007