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.

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

“…Furthermore, our results demonstrate that cerebral synthesis of proinflammatory cytokines as observed in some animal models for HE is not solely explained by hyperammonemia (16,31), in line with previous data (13,14). Consistent with the present findings, data derived from postmortem human brain samples consistently show no up-regulation of proinflammatory cytokine mRNA or protein in the brain tissue of patients with liver cirrhosis and HE (32,52,54).…”

Analytical fusion of multimodal magnetic resonance imaging to identify pathological states in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats

“…recently proposed as a mechanism of alcohol-related brain damage (160,161). If this were the case, the changes induced in the structure of brain parenchyma by a neuroinflammatory process, affecting the tortuosity and/or volume of the extracellular space, or inducing iron accumulation (34,40,46,47) would help explain some of the individual MRI alterations found in our study.…”

“…Sheu reports associations between T2 in dopamine targets regions (caudate, putamen, thalamus and dorsolateral prefrontal cortex, nucleus accumbens, substantia nigra) and the use of the drugs and alcohol (44). As well, iron and microglia activation in the brain accumulation (45)(46)(47) associated to alcoholism has been established as a cause of reduction (shortening) in T2 relaxation times (48). As well as structural changes, functional reorganization has been probed.…”

PET and MR imaging of neuroinflammation in hepatic encephalopathy

“…Except microglial activation, microglial proliferation was found in patients with chronic alcoholics cirrhosis and HE (Dennis et al 2014). The microglia in these patients displayed an activated morphology with hypertrophied cell bodies and short, thickened processes.…”