The Cerebellum of Patients with Steatohepatitis Shows Lymphocyte Infiltration, Microglial Activation and Loss of Purkinje and Granular Neurons

Abstract

Peripheral inflammation contributes to minimal hepatic encephalopathy in chronic liver diseases, which could be mediated by neuroinflammation. Neuroinflammation in cerebellum of patients with chronic liver diseases has not been studied in detail. Our aim was to analyze in cerebellum of patients with different grades of liver disease, from mild steatohepatitis to cirrhosis and hepatic encephalopathy: (a) neuronal density in Purkinje and granular layers; (b) microglial activation; (c) astrocyte activation; (d) peripheral lymphocytes infiltration; (e) subtypes of lymphocytes infiltrated. Steatohepatitis was classified as SH1, SH2 and SH3. Patients with SH1 show Th17 and Tfh lymphocytes infiltration in the meninges, microglia activation in the molecular layer and loss of 16 ± 4% of Purkinje and 19 ± 2% of granular neurons. White matter remains unaffected. With the progression of liver disease to worse stages (SH2, SH3, cirrhosis) activation of microglia and astrocytes extends to white matter, Bergman glia is damaged in the molecular layer and there is a further loss of Purkinje neurons. The results reported show that neuroinflammation in cerebellum occurs at early stages of liver disease, even before reaching cirrhosis. Neuroinflammation occurs earlier in the molecular layer than in white matter, and is associated with infiltration of peripheral Th17 and Tfh lymphocytes.

Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications

“…Patients with SH2, SH3 or cirrhosis showed activated microglia both in the molecular layer and white matter. These findings suggested that activation of microglia and neuroinflammation progresses from the molecular layer to white matter …”

“…The findings reported by Balzano et al, summarized in Figure , suggested that in patients with low grade steatohepatitis, there is an infiltration of T lymphocytes, especially Th17, Tfh and autoreactive CD4 + CD28 − T lymphocytes, into cerebellar meninges. This infiltration has been associated with early microglia activation in molecular layer, as early as stage SH1 and Bergmann glia alterations, which would contribute to neuronal degeneration in the Purkinje and granular layers.…”

“…The cerebellum of patients with chronic liver disease showed activation of astrocytes in the white matter, which started in the SH2 stage of liver disease and was also activated in the SH3 stage and cirrhosis. Bergmann glia, a special type of astrocyte in the molecular layer, was also damaged in chronic liver disease …”

“…We observed a relevant number of images in which activated microglia seemed to be “eating” a Purkinje neuron. This suggested that phagoptosis by activated microglia contributed to reducing the number of Purkinje neurons in liver disease …”

“…This infiltration has been associated with early microglia activation in molecular layer, as early as stage SH1 and Bergmann glia alterations, which would contribute to neuronal degeneration in the Purkinje and granular layers. These changes, in turn, could lead to white matter glial activation in SH2, SH3 and cirrhosis …”