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.

Reactive astrocytes targeting with oral vitamin A: Efficient neuronal regeneration for Parkinson's disease treatment and reversal of associated liver fibrosis

“…According to our findings, haloperidol‐induced PD was associated with significant fibrous tissue deposition, representing Ishak score 3, and significantly increased levels of two key fibrosis markers; TGF‐β the strongest inducer of fibrotic diseases and hydroxyproline, a main collagen constituent that acts as a good extracellular matrix accumulation marker 20 . In accordance, a positive correlation between PD and liver dysfunction was perceived in various clinical studies that confirmed an association between PD and cirrhosis 42–44 . In addition, liver impairment and liver enzymes abnormalities were found to exist in patients with PD 45 .…”

“… 20 In accordance, a positive correlation between PD and liver dysfunction was perceived in various clinical studies that confirmed an association between PD and cirrhosis. 42 , 43 , 44 In addition, liver impairment and liver enzymes abnormalities were found to exist in patients with PD. 45 PD‐associated hepatic fibrosis may be a consequence of brain V A deficiency.…”

Literature-Based Discovery Predicts Antihistamines Are a Promising Repurposed Adjuvant Therapy for Parkinson’s Disease

“…Additionally, a retrospective cohort study of various types of hepatitis reported increased rates of subsequent PD in individuals with hepatitis B and hepatitis C [50]. Growing evidence suggests that the prevalence of liver disease history among PD patients is connected to the inability of the liver to clear the blood of neurotoxins like α-syn and manganese (Mn), which can then accumulate in the liver [51,52]. Compromised hepatic ability resulting from liver disease may sabotage the removal of pathological proteins, allowing neurotoxins to enter cerebral circulation and facilitate PD pathogenesis [52].…”

“…Growing evidence suggests that the prevalence of liver disease history among PD patients is connected to the inability of the liver to clear the blood of neurotoxins like α-syn and manganese (Mn), which can then accumulate in the liver [51,52]. Compromised hepatic ability resulting from liver disease may sabotage the removal of pathological proteins, allowing neurotoxins to enter cerebral circulation and facilitate PD pathogenesis [52]. The entrance of toxic substances into the brain is further provoked by portosystemic shunting, which often occurs as a result of advanced liver diseases like acquired hepatocerebral degeneration (ADH) [52].…”

Evaluation and Management of Nutritional Consequences of Chronic Liver Diseases

“…Magnesium deficiency occurs due to the malabsorption of magnesium in the small intestine, is exacerbated by diuretic use, and is correlated with diminished muscle strength and reduced cognitive ability in adults with cirrhosis [32]. Elevated manganese levels in patients with cirrhosis have been related to selective manganese accumulation in the basal ganglia, resulting in extrapyramidal and neuropsychiatric symptoms [33]. Specific evidence regarding the advantageous impact of micronutrients and vitamin supplementation in cirrhotic patients is not available.…”