Brain metal concentrations in chronic liver failure patients with pallidal T1 MRI hyperintensity

Background: Chronic liver failure may be associated with pallidal MRI T1 hyperintensity and heterogeneous neurologic syndromes, including parkinsonism, cognitive impairment, and others. Manganese accumulation may be responsible for the imaging and clinical findings. Objective: To measure manganese plus other metal concentrations in pallidum and additional brain regions and to examine the corresponding neuropathology in cases of chronic liver failure. Methods: Regional brain metal concentrations were measured in seven chronic liver failure cases, four with pallidal T1 hyperintensity and three with normal MRI, plus five controls. Neuropathologic examination employed α-synuclein and tau immunohistochemistry. Results: In patients with pallidal T1 hyperintensity, pallidal manganese concentrations were increased sevenfold over controls and over fourfold vs liver patients with normal MRI; manganese concentrations were also significantly elevated in all other brain regions. Copper was additionally increased in all brain regions, whereas other metal concentrations were similar to control values. Neuropathology revealed mild to moderate Alzheimer type II gliosis in the liver failure groups and negative α-synuclein and tau immunostaining except for one case (intermediate Alzheimer disease pathology). Conclusion: In chronic liver failure, manganese accumulation is responsible for the pallidal MRI T1 hyperintensity. Pallidal copper was also elevated in affected cases, but copper does not have the paramagnetic properties to generate isolated T1 hyperintensity. Basal ganglia manganese or copper accumulation may be responsible for the parkinsonism sometimes seen in chronic liver failure. Pallidal MRI T1 hyperintensity is a biomarker of manganese overload.