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Metabolic Brain Disease

, Volume 29, Issue 4, pp 1027–1039 | Cite as

Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy

  • Claude V. Dennis
  • Pamela J. Sheahan
  • Manuel B. Graeber
  • Donna L. Sheedy
  • Jillian J. Kril
  • Greg T. SutherlandEmail author
Original Paper

Abstract

Hepatic encephalopathy (HE) is a common complication of chronic alcoholism and patients show neurological symptoms ranging from mild cognitive dysfunction to coma and death. The HE brain is characterized by glial changes, including microglial activation, but the exact pathogenesis of HE is poorly understood. During a study investigating cell proliferation in the subventricular zone of chronic alcoholics, a single case with widespread proliferation throughout their adjacent grey and white matter was noted. This case also had concomitant HE raising the possibility that glial proliferation might be a pathological feature of the disease. In order to explore this possibility fixed postmortem human brain tissue from chronic alcoholics with cirrhosis and HE (n = 9), alcoholics without HE (n = 4) and controls (n = 4) were examined using immunohistochemistry and cytokine assays. In total, 4/9 HE cases had PCNA- and a second proliferative marker, Ki-67-positive cells throughout their brain and these cells co-stained with the microglial marker, Iba1. These cases were termed ‘proliferative HE’ (pHE). The microglia in pHEs displayed an activated morphology with hypertrophied cell bodies and short, thickened processes. In contrast, the microglia in white matter regions of the non-proliferative HE cases were less activated and appeared dystrophic. pHEs were also characterized by higher interleukin-6 levels and a slightly higher neuronal density . These findings suggest that microglial proliferation may form part of an early neuroprotective response in HE that ultimately fails to halt the course of the disease because underlying etiological factors such as high cerebral ammonia and systemic inflammation remain.

Keywords

Alcoholism Human brain Encephalopathy Liver disease Microglial proliferation 

Notes

Acknowledgments

The authors would like to thank the donors and their families for their kind gift that has allowed this research to be undertaken and the New South Wales Tissue Resource Centre (NSW TRC) for providing tissue samples. We would like to acknowledge Dr. Louise Cole (Core Facilities Manager, Bosch Institute Advanced Microscopy Facility, The University of Sydney) for her support and assistance with the confocal microscopy and Dr. Donna Lai for her assistance with performing cytokine ELISAs. The NSW TRC is part of the NSW Brain Bank Network and Australian Brain Bank Network and is supported by the University of Sydney, National Health and Medical Research Council (NHMRC), Schizophrenia Research Institute and the National Institutes of Alcoholism and Alcohol Abuse (NIAAA). This work was supported by the NIAAA (R24 AA012725) and the NHMRC (grant #605210).

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Claude V. Dennis
    • 1
  • Pamela J. Sheahan
    • 1
  • Manuel B. Graeber
    • 2
    • 3
    • 4
  • Donna L. Sheedy
    • 1
  • Jillian J. Kril
    • 1
    • 2
  • Greg T. Sutherland
    • 1
    • 5
    Email author
  1. 1.Discipline of PathologySydney Medical SchoolCamperdownAustralia
  2. 2.Discipline of MedicineSydney Medical SchoolCamperdownAustralia
  3. 3.Brain and Mind Research InstituteSydney Medical SchoolCamperdownAustralia
  4. 4.Faculty of Health SciencesUniversity of SydneyCamperdownAustralia
  5. 5.Discipline of PathologyUniversity of SydneySydneyAustralia

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