title: Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy.
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.
authors.affiliation: Discipline of Pathology, Sydney Medical School, Camperdown, NSW, 2050, Australia.
authors.forename: Claude V
authors.initials: CV
authors.lastname: Dennis
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Sheahan
authors.forename: Manuel B
authors.initials: MB
authors.lastname: Graeber
authors.forename: Donna L
authors.initials: DL
authors.lastname: Sheedy
authors.forename: Jillian J
authors.initials: JJ
authors.lastname: Kril
authors.forename: Greg T
authors.initials: GT
authors.lastname: Sutherland
mesh_terms: D000437:Alcoholism / Q000150:complications / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry; D002452:Cell Count; D002455:Cell Division; D016207:Cytokines / Q000032:analysis; D005260:Female; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000473:pathology*; D006801:Humans; D006984:Hypertrophy; D019394:Ki-67 Antigen / Q000032:analysis; D008104:Liver Cirrhosis, Alcoholic / Q000473:pathology; D008297:Male; D017628:Microglia / Q000473:pathology*; D008875:Middle Aged; D009474:Neurons / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012907:Smoking / Q000473:pathology; D066127:White Matter / Q000473:pathology
chemical_list: D016207:Cytokines; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen