Manganese, a Likely Cause of 'Parkinson's in Cirrhosis', a Unique Clinical Entity of Acquired Hepatocerebral Degeneration

Abstract

With idiopathic Parkinson's disease being a common entity, parkinsonism in acquired hepatocerebral degeneration (AHD) in the context of Manganese (Mn) has gained importance in recent years. An insight into the pathomechanisms behind this disease has been put forth. How can Mn as a divalent metal exert its effect in leading to chronic neurodegenerative disorder? Secondary to decreased excretion in liver cirrhosis, Mn significantly alters the striatal dopaminergic system. Management of this debilitating disease also focuses on different aspects where Mn has been involved in the pathogenesis. We have put forth the details behind Mn effects in Parkinson's, which will be a guide for better understanding and management of this disease. A literature search was performed using PubMed as a sole database, and all the articles were peer-reviewed. The author tried to follow the PRISMA guidelines. Inclusion criteria were set for 10 years, with most studies with in the last seven years. All types of study designs were included relevant to the topic, clearly delineating the pathomechanisms of Mn in the disease and also its management. After extensive research, through the PubMed database, we found that Parkinson's disease is one of the neurological complications in advanced liver cirrhosis. Mn is an essential element behind its pathogenesis; it works at different cellular levels to promote neurotoxicity. From its influx to its effects on dopamine transporters (DAT), where it disrupts dopamine homeostasis also altering postsynaptic dopamine (D2) receptors, it disrupts mitochondria and the endoplasmic reticulum (ER) promotes oxidative stress and neuroinflammation. Misfolding of alpha-synuclein (α-Syn) is promoted on chronic exposure to Mn where α-Syn from being neuroprotective becomes neurotoxic. It also alters glutaminergic and gabaergic neurotransmission. In a nutshell, the diversity of its effect on nigrostriatal denervation is challenging. The importance of neuroimaging and various approaches to management is also discussed. AHD, an uncommon entity in advanced liver cirrhosis, needs more awareness so that it can be diagnosed earlier and better therapeutic options can be sought. Our study highlighted Mn mechanisms behind this clinical entity, putting forth grounds for a better understanding of this disease. Advanced research targeting Mn for managing this disease will be revolutionary.

Keywords: acquired hepatocerebral degeneration; acquired hepatolenticular degeneration; dopamine in liver cirrhosis; liver cirrhosis; manganese and chronic liver disease; manganese and dopamine; manganese and dopamine transporter; neurological manifestation of chronic liver disease; parkinson cirrhosis; parkinsons disease.

Figure 1. PRISMA flow diagram for study selection.

PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analysis

Figure 2. Role of manganese in acquired hepatocerebral degeneration. The idea for the figure was adopted from the article ' Recent Updates on Acquired Hepatocerebral Degeneration'. However, this figure was modified according to our study's requirement.

Mn: manganese; Cyt-c: cytochrome C; DAT: dopamine transporter; IL1 beta: interleukin 1 beta; IL6: interleukin 6; α-Syn: alpha-synuclein

Figure 3. Treatment options for acquired hepatocerebral degeneration.

Mn: Manganese; ROS: reactive oxygen species; GGC: glutamine/glutamate GABA cycle