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Role of manganese in the pathogenesis of portal-systemic encephalopathy
G P Layrargues1, C Rose, L Spahr
1Liver Unit, Clinical Research Center, CHUM, Montreal, Québec, Canada. pomierlg@ere.montreal.ca
Abstract:
Amongst the potential neurotoxins implicated in the pathogenesis of hepatic encephalopathy, manganese emerges as a new candidate. In patients with chronic liver diseases, manganese accumulates in blood and brain leading to pallidal signal hyperintensity on T1-weighted Magnetic Resonance (MR) Imaging. Direct measurements in globus pallidus obtained at autopsy from cirrhotic patients who died in hepatic coma reveal 2 to 7-fold increases of manganese concentration. The intensity of pallidal MR images correlates with blood manganese and with the presence of extrapyramidal symptoms occurring in a majority of cirrhotic patients. Liver transplantation results in normalization of pallidal MR signals and disappearance of extrapyramidal symptoms whereas transjugular intrahepatic portosystemic shunting induces an increase in pallidal hyperintensity with a concomitant deterioration of neurological dysfunction. These findings suggest that the toxic effects of manganese contribute to extrapyramidal symptoms in patients with chronic liver disease. The mechanisms of manganese neurotoxicity are still speculative, but there is evidence to suggest that manganese deposition in the pallidum may lead to dopaminergic dysfunction. Future studies should be aimed at evaluating the effects of manganese chelation and/or of treatment of the dopaminergic deficit on neurological symptomatology in these patients.
Insights
Manganese accumulation in the brain contributes to neurological symptoms in chronic liver disease patients. Reducing manganese levels can improve these symptoms and brain imaging results.
Area of Science:
- Neuroscience
- Hepatology
- Radiology
Background:
- Hepatic encephalopathy is a complex neurological complication of chronic liver disease.
- Manganese is increasingly recognized as a potential neurotoxin contributing to liver disease-related neurological dysfunction.
- Elevated manganese levels in chronic liver disease patients are linked to characteristic brain MRI signal changes.
Purpose of the Study:
- To investigate the role of manganese accumulation in the pathogenesis of neurological symptoms in chronic liver disease.
- To correlate brain manganese levels with clinical symptoms and neuroimaging findings.
- To assess the impact of interventions like liver transplantation and shunting on manganese deposition and neurological function.
Main Methods:
- Analysis of manganese concentration in the globus pallidus post-mortem in cirrhotic patients.
- Correlation of pallidal signal intensity on T1-weighted Magnetic Resonance (MR) Imaging with blood manganese levels and extrapyramidal symptoms.
- Evaluation of changes in MR signals and neurological function following liver transplantation and transjugular intrahepatic portosystemic shunting (TIPS).
Main Results:
- Autopsy studies revealed 2- to 7-fold increases in globus pallidus manganese concentration in cirrhotic patients.
- Pallidal MR image intensity correlated significantly with blood manganese levels and the presence of extrapyramidal symptoms.
- Liver transplantation normalized pallidal MR signals and resolved extrapyramidal symptoms, while TIPS worsened them.
Conclusions:
- Manganese neurotoxicity contributes significantly to extrapyramidal symptoms in patients with chronic liver disease.
- Manganese deposition in the pallidum may induce dopaminergic dysfunction, underlying the observed neurological deficits.
- Further research should explore manganese chelation and dopaminergic deficit treatment for neurological symptom management.