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Zolin A, Ooi H, Zhou M, Su C, Wang F, Sarva H. Liver fibrosis associated with more severe motor deficits in early Parkinson's disease. Clin Neurol Neurosurg 2025; 252:108861. [PMID: 40154229 DOI: 10.1016/j.clineuro.2025.108861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025]
Abstract
OBJECTIVE To determine the impact of hepatic dysfunction on the motor manifestations of Parkinson's disease. METHODS We conducted a retrospective cohort study using data from the Parkinson's Progression Markers Initiative. Liver fibrosis was defined using the Fibrosis-4 score. Our primary outcome was the association of baseline Fibrosis-4 score with the Movement Disorders Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score. Additional outcomes were MDS-UPDRS part II, MDS-UPDRS part IV, Hoehn and Yahr stage, and levodopa equivalent daily dose. We used linear regression models to evaluate associations at baseline and 5 years after enrollment. We used linear mixed models to evaluate the association of liver fibrosis with the progression of motor dysfunction. Models were adjusted for demographics, comorbidities, alcohol use, time since Parkinson's disease diagnosis, levodopa equivalent daily dose, and genetic predisposition. RESULTS We included 360 people with Parkinson's disease with a mean age of 61.8 years (standard deviation 9.7) and 41.1 % women. There was a significant association between liver fibrosis and baseline MDS-UPDRS part III score (β=2.3, 95 % CI: 0.2, 4.5). Liver fibrosis was also correlated with higher interhemispheric signal asymmetry on DAT-SPECT scans in the anterior putamen (p < 0.05 by Wilcoxon rank sum test). There was no correlation with Fibrosis-4 score and any other motor assessment at baseline or after 5 years. Patients with elevated Fibrosis-4 scores had a slower rate of progression in MDS-UPDRS part III scores. CONCLUSION In people with Parkinson's disease, the presence of comorbid liver fibrosis was associated with more severe motor dysfunction early, but not later, within their disease course.
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Affiliation(s)
- Aryeh Zolin
- Parkinson's Disease and Movement Disorders Institute, Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
| | - Hwai Ooi
- Parkinson's Disease and Movement Disorders Institute, Department of Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Manqi Zhou
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA; Department of Computational Biology, Cornell University, Ithaca, NY, USA
| | - Chang Su
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Fei Wang
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Harini Sarva
- Parkinson's Disease and Movement Disorders Institute, Department of Neurology, Weill Cornell Medicine, New York, NY, USA
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He X, Hu M, Xu Y, Xia F, Tan Y, Wang Y, Xiang H, Wu H, Ji T, Xu Q, Wang L, Huang Z, Sun M, Wan Y, Cui P, Liang S, Pan Y, Xiao S, He Y, Song R, Yan J, Quan X, Wei Y, Hong C, Liao W, Li F, El-Omar E, Chen J, Qi X, Gao J, Zhou H. The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis. Nat Med 2025; 31:627-638. [PMID: 39779925 DOI: 10.1038/s41591-024-03405-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 11/07/2024] [Indexed: 01/11/2025]
Abstract
Up to 50-70% of patients with liver cirrhosis develop hepatic encephalopathy (HE), which is closely related to gut microbiota dysbiosis, with an unclear mechanism. Here, by constructing gut-brain modules to assess bacterial neurotoxins from metagenomic datasets, we found that phenylalanine decarboxylase (PDC) genes, mainly from Ruminococcus gnavus, increased approximately tenfold in patients with cirrhosis and higher in patients with HE. Cirrhotic, not healthy, mice colonized with R. gnavus showed brain phenylethylamine (PEA) accumulation, along with memory impairment, symmetrical tremors and cortex-specific neuron loss, typically found in patients with HE. This accumulation of PEA was primarily driven by decreased monoamine oxidase-B activity in both the liver and serum due to cirrhosis. Targeting PDC or PEA reversed the neurological symptoms induced by R. gnavus. Furthermore, fecal microbiota transplantation from patients with HE to germ-free cirrhotic mice replicated these symptoms and further corroborated the efficacy of targeting PDC or PEA. Clinically, high baseline PEA levels were linked to a sevenfold increased risk of HE after intrahepatic portosystemic shunt procedures. Our findings expand the understanding of the gut-liver-brain axis and identify a promising therapeutic and predictive target for HE.
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Affiliation(s)
- Xiaolong He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Mengyao Hu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yi Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fangbo Xia
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Tan
- Shandong Provincial Key Laboratory of Synthetic Biology, Qingdao C1 Refinery Engineering Research Center, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China
| | - Yuqing Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Huiling Xiang
- Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Tengfei Ji
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qian Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhenhe Huang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Meiling Sun
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yu Wan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Peng Cui
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shaocong Liang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Pan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Siyu Xiao
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China
| | - Ruixin Song
- The Third Central Clinical College of Tianjin Medical University, Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China
| | - Junqing Yan
- Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China
| | - Xin Quan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yingge Wei
- Department of Hepatology, Third People's Hospital of Linfen City, Linfen, China
| | - Changze Hong
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weizuo Liao
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, the State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Fuli Li
- Shandong Provincial Key Laboratory of Synthetic Biology, Qingdao C1 Refinery Engineering Research Center, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China
| | - Emad El-Omar
- UNSW Microbiome Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW SYDNEY, Sydney, New South Wales, Australia
| | - Jinjun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Xiaolong Qi
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
| | - Jie Gao
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
- The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, the State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
| | - Hongwei Zhou
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China.
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China.
- Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China.
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
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Kollaparampil Kishanchand D, K A AK, Chandrababu K, Philips CA, Sivan U, Pulikaparambil Sasidharan BC. The Intricate Interplay: Microbial Metabolites and the Gut-Liver-Brain Axis in Parkinson's Disease. J Neurosci Res 2025; 103:e70016. [PMID: 39754366 DOI: 10.1002/jnr.70016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 11/21/2024] [Accepted: 12/23/2024] [Indexed: 01/06/2025]
Abstract
Parkinson's Disease (PD) is a neurodegenerative disorder marked by the depletion of dopaminergic neurons. Recent studies highlight the gut-liver-brain (GLB) axis and its role in PD pathogenesis. The GLB axis forms a dynamic network facilitating bidirectional communication between the gastrointestinal tract, liver, and central nervous system. Dysregulation within this axis, encompassing gut dysbiosis and microbial metabolites, is emerging as a critical factor influencing PD progression. Our understanding of PD was traditionally centered on neurodegenerative processes within the brain. However, examining PD through the lens of the GLB axis provides new insights. This review provides a comprehensive analysis of microbial metabolites, such as short-chain fatty acids (SCFAs), trimethylamine-N-oxide (TMAO), kynurenine, serotonin, bile acids, indoles, and dopamine, which are integral to PD pathogenesis by modulation of the GLB axis. Our extensive research included a comprehensive literature review and database searches utilizing resources such as gutMGene and gutMDisorder. These databases have been instrumental in identifying specific microbes and their metabolites, shedding light on the intricate relationship between the GLB axis and PD. This review consolidates existing knowledge and underscores the potential for targeted therapeutic interventions based on the GLB axis and its components, which offer new avenues for future PD research and treatment strategies. While the GLB axis is not a novel concept, this review is the first to focus specifically on its role in PD, highlighting the importance of integrating the liver and microbial metabolites as central players in the PD puzzle.
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Affiliation(s)
| | - Athira Krishnan K A
- Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Kochi, Kerala, India
| | - Krishnapriya Chandrababu
- Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Kochi, Kerala, India
| | - Cyriac Abby Philips
- Clinical and Translational Hepatology, The Liver Institute, Centre of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Unnikrishnan Sivan
- Department of FSQA, FFE, Kerala University of Fisheries and Ocean Studies, Kochi, Kerala, India
| | - Baby Chakrapani Pulikaparambil Sasidharan
- Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Kochi, Kerala, India
- Centre for Excellence in Neurodegeneration and Brain Health, Kochi, Kerala, India
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Smith ML, Wade JB, Wolstenholme J, Bajaj JS. Gut microbiome-brain-cirrhosis axis. Hepatology 2024; 80:465-485. [PMID: 36866864 PMCID: PMC10480351 DOI: 10.1097/hep.0000000000000344] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/10/2023] [Indexed: 03/04/2023]
Abstract
Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.
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Affiliation(s)
- Maren L Smith
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - James B Wade
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jennifer Wolstenholme
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
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Sigawi T, Hamtzany O, Hurvitz N, Ishay Y, Dayan R, Arkadir D, Ilan Y. Investigating the Relationship between Chronic Liver Cirrhosis and Parkinsonism: A Comparative Analysis and a Suggested Diagnostic Scheme. Clin Pract 2024; 14:1375-1382. [PMID: 39051304 PMCID: PMC11270255 DOI: 10.3390/clinpract14040110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 06/28/2024] [Accepted: 07/08/2024] [Indexed: 07/27/2024] Open
Abstract
Aim: Neurological manifestations are common in patients with chronic liver diseases. This study aimed to depict the association between liver cirrhosis and Parkinson's disease (PD) and propose a clinically relevant diagnostic scheme. Methods: We examined patients' medical records with PD and chronic liver impairment secondary to cirrhosis or liver metastases for temporal correlations between liver insult and Parkinsonian signs. Results: Thirty-five individuals with PD and chronic liver impairment were included due to either cirrhosis or liver metastases. In all 22 patients with PD and liver metastases, the diagnosis of PD preceded the diagnosis of cancer. Conversely, patients with cirrhosis were often diagnosed with liver impairment before diagnosing PD. Age at diagnosis did not account for this difference. Conclusions: This study reinforces the potential clinical association between cirrhosis and PD. We also provide a diagnostic scheme that may guide therapeutic interventions and prognostic assessments.
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Affiliation(s)
- Tal Sigawi
- Department of Medicine, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem 9112001, Israel; (T.S.); (O.H.); (N.H.); (Y.I.)
| | - Omer Hamtzany
- Department of Medicine, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem 9112001, Israel; (T.S.); (O.H.); (N.H.); (Y.I.)
| | - Noa Hurvitz
- Department of Medicine, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem 9112001, Israel; (T.S.); (O.H.); (N.H.); (Y.I.)
| | - Yuval Ishay
- Department of Medicine, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem 9112001, Israel; (T.S.); (O.H.); (N.H.); (Y.I.)
| | - Roy Dayan
- Department of Neurology, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem 9112001, Israel; (R.D.); (D.A.)
| | - David Arkadir
- Department of Neurology, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem 9112001, Israel; (R.D.); (D.A.)
| | - Yaron Ilan
- Department of Medicine, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem 9112001, Israel; (T.S.); (O.H.); (N.H.); (Y.I.)
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Mukund A, Premkumar M, Srivastava A, Baby A, Patidar Y, Sarin S. Partial Reversal of Shunt Myelopathy and Hepatic Parkinsonism Using Balloon-Occluded Retrograde Transvenous Obliteration. Cardiovasc Intervent Radiol 2024; 47:847-851. [PMID: 38649445 DOI: 10.1007/s00270-024-03729-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 04/04/2024] [Indexed: 04/25/2024]
Affiliation(s)
- Amar Mukund
- Interventional Radiology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, India.
| | - Madhumita Premkumar
- Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, India
| | - Amol Srivastava
- Interventional Radiology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, India
| | - Akhil Baby
- Interventional Radiology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, India
| | - Yashwant Patidar
- Interventional Radiology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, India
| | - Shiv Sarin
- Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, India
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Dubey A, Kumar S, Acharya S, Nagendra V, Khurana K. Acquired Parkinson's Disease in Alcoholic Cirrhosis: The Rarest Association. Cureus 2023; 15:e34968. [PMID: 36938289 PMCID: PMC10019375 DOI: 10.7759/cureus.34968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 02/14/2023] [Indexed: 02/16/2023] Open
Abstract
Hepatic encephalopathy is the most common neurologic complication of liver cirrhosis, whereas acquired hepatocerebral degeneration (AHD) is an underappreciated neurologic manifestation. Parkinsonism, ataxia, and neuropsychiatric symptoms are its defining characteristics. In individuals with chronic parenchymal liver disease with portosystemic shunting, it is an underrecognized etiology of psychomotor retardation. It has been hypothesized that the etiology of AHD is due to manganese buildup in the basal ganglia. This case report details a hepatocerebral degeneration (AHD) case in a patient with chronic parenchymal liver disease who improved after taking a dopamine agonist.
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Affiliation(s)
- Apurva Dubey
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Sunil Kumar
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Sourya Acharya
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
| | - Vadlamudi Nagendra
- Department of Radiology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, IND
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Liu J, Tan L, Liu Z, Shi R. Blood and urine manganese exposure in non-alcoholic fatty liver disease and advanced liver fibrosis: an observational study. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:22222-22231. [PMID: 36280639 DOI: 10.1007/s11356-022-23630-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 10/10/2022] [Indexed: 06/16/2023]
Abstract
Manganese was the key activator of biological enzymes-mediated metabolic diseases (Mets)-associated pathophysiological process. Non-alcoholic fatty liver disease (NAFLD), which was the hepatic manifestation of Mets, development remained a mystery. We aimed to explore the association between blood/urine manganese exposure and NAFLD and liver fibrosis diagnosed by vibration-controlled transient elastography (VCTE). All data were extracted from National Health and Nutrition Examination Survey database (2017-2018). A total of 3580 participants with blood manganese data were enrolled and divided into four groups according to the quartile of blood manganese exposure level. In multiple logistic regression models, the higher blood manganese exposure level (groups 2, 3, and 4) had a significant positive association with NAFLD (β = 1.58, 1.30, and 1.69). In subgroup analysis, the main inversely correlation between blood manganese and NAFLD was found in participants with normal/high body mass index and high blood manganese exposure level. Moreover, in 1179 participants with urine manganese data, urine manganese exposure level presented as significantly associated with advanced liver fibrosis in models 1 and 2 (β = 2.00 and 2.02). This study showed that manganese exposure level was positively associated with NAFLD and advanced liver fibrosis among the US population. We suggested that manganese exposure level was a biomarker of the development of NAFLD.
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Affiliation(s)
- Jie Liu
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liao Tan
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoya Liu
- Department of the Geriatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ruizheng Shi
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Mohammed A, Bane A, Mengistu G, Ayalew F, Seid AS. Acquired Hepatocerebral Degeneration After a Splenorenal Shunt in the Sub-Saharan Africa Context: A Case Report and Brief Review of Literature. Cureus 2022; 14:e23064. [PMID: 35464550 PMCID: PMC9001859 DOI: 10.7759/cureus.23064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2022] [Indexed: 11/10/2022] Open
Abstract
Acquired hepatocerebral degeneration (AHD) is a neurologic syndrome caused by liver dysfunction and long-standing portosystemic shunting. The pathogenesis of the condition is predominantly considered to be related to the deposition of manganese in parts of the brain due to shunting. We report a case of a 25-year-old male who underwent splenectomy and splenorenal shunt for recurrent upper GI bleeding (UGIB) due to esophageal varices caused by non-cirrhotic portal hypertension (NCPH). He presented with bradykinesia, hypophonia, gait instability, and rigidity of the lower extremities 18 months after the procedure was done.
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Gurol KC, Aschner M, Smith DR, Mukhopadhyay S. Role of excretion in manganese homeostasis and neurotoxicity: a historical perspective. Am J Physiol Gastrointest Liver Physiol 2022; 322:G79-G92. [PMID: 34786983 PMCID: PMC8714252 DOI: 10.1152/ajpgi.00299.2021] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The essential metal manganese (Mn) induces incurable neurotoxicity at elevated levels that manifests as parkinsonism in adults and fine motor and executive function deficits in children. Studies on Mn neurotoxicity have largely focused on the role and mechanisms of disease induced by elevated Mn exposure from occupational or environmental sources. In contrast, the critical role of excretion in regulating Mn homeostasis and neurotoxicity has received less attention although 1) studies on Mn excretion date back to the 1920s; 2) elegant radiotracer Mn excretion assays in the 1940s to 1960s established the routes of Mn excretion; and 3) studies on patients with liver cirrhosis in the 1990s to 2000s identified an association between decreased Mn excretion and the risk of developing Mn-induced parkinsonism in the absence of elevated Mn exposure. Notably, the last few years have seen renewed interest in Mn excretion largely driven by the discovery that hereditary Mn neurotoxicity due to mutations in SLC30A10 or SLC39A14 is caused, at least in part, by deficits in Mn excretion. Quite remarkably, some of the recent results on SLC30A10 and SLC39A14 provide explanations for observations made ∼40-50 years ago. The goal of the current review is to integrate the historic studies on Mn excretion with more contemporary recent work and provide a comprehensive state-of-the-art overview of Mn excretion and its role in regulating Mn homeostasis and neurotoxicity. A related goal is to discuss the significance of some of the foundational studies on Mn excretion so that these highly consequential earlier studies remain influential in the field.
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Affiliation(s)
- Kerem C. Gurol
- 1Division of Pharmacology & Toxicology, College of Pharmacy, and Institute for Neuroscience, The University of Texas at Austin, Austin, Texas
| | - Michael Aschner
- 2Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York
| | - Donald R. Smith
- 3Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, California
| | - Somshuvra Mukhopadhyay
- 1Division of Pharmacology & Toxicology, College of Pharmacy, and Institute for Neuroscience, The University of Texas at Austin, Austin, Texas
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11
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Reinert JP, Garner M, Forbes L. Hypermanganesemia-Induced Cerebral Toxicity Mimicking an Acute Ischemic Stroke: A Case Report and Review of Overlapping Pathologies. J Pharm Technol 2021; 37:127-132. [PMID: 34752535 DOI: 10.1177/8755122520976418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective: To review and consider risk factors associated with the accumulation of and toxicity from manganese in patients receiving total parenteral nutrition (TPN). Case Summary: A 66-year-old female presented to the emergency department with right facial and arm weakness that initiated 1 hour prior to admission. Past medical history includes oral cancer with chronic aspiration and gastroparesis secondary to chemotherapy, TPN for 9 months, and a previous episode of right facial and arm parasthesias due to hypertensive emergency 4 years prior. The patient was assigned a National Institutes of Health Stroke Scale score of 6, cleared of an intracranial hemorrhage on imaging, and was administered tPA (tissue plasminogen activator) for an acute ischemic stroke after managing her hypertension to <185/110 mm Hg. Resolution of symptoms occurred within 24 hours. A magnetic resonance imaging of the patient's brain 24-hours post-tPA indicated an increased signal density in the globus pallidus, which in turn is linked with encephalopathy and has been described as a marker for hypermanganesemia. Discussion: Manganese is an essential trace element with a critical role in numerous physiologic functions. Though readily obtained from dietary sources and rarely causing issue, manganese provided to patients via TPN may result in toxicities. Though the presentation of neurotoxicities associated with TPN-delivered manganese has been previously documented, the clinical presentation of toxicity has never mimicked an acute ischemic stroke. Conclusion: Though an evaluation of overlapping pathologies is warranted, this patient's clinical presentation of manganese toxicity mimicked an acute ischemic stroke and resulted in the administration of a fibrinolytic. A more comprehensive appreciation of the implications of trace elements is demanded of clinicians.
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12
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Reinert JP, Forbes LD. Manganese Toxicity Associated With Total Parenteral Nutrition: A Review. J Pharm Technol 2021; 37:260-266. [PMID: 34753157 PMCID: PMC8404746 DOI: 10.1177/87551225211023686] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objective: To review hypermanganesemia-induced toxicities in adult patients receiving parenteral nutrition (PN) therapy. Data Sources: A comprehensive literature review was conducted from June 2020 to May 2021 on PubMED, MEDLINE, Scopus, ProQuest, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Web of Science. Study Selection and Data Extraction: Keyword and Boolean phrase searches were conducted using the following terminology: "manganese" OR "manganesemia" OR "manganism" or "hypermanganesemia" AND "total parenteral nutrition" OR "PN" or "parenteral nutrition" AND "toxicity" OR "accumulation." Appropriate filters, including "humans" and "English" and NOT "reviews," were utilized on all databases to improve search outcomes. Data Synthesis: A total of 4 reports detailing hypermanganesemia in 57 patient encounters were included in this review. Significant heterogeneity exists with regard to the duration of manganese supplementation and the dose of manganese. Toxicity associated with manganese was observed in as few as 15 days. The dose of manganese, though likely governed by content in commercially available products, may regularly exceed the recommendations of clinical guidelines and should be limited to 55 µg/day. Select patients with underlying malignancy, those with significant and prolonged Vitamin D deficiency, or those who have acquired a SLC30A10 genetic mutation may be at an increased risk of developing manganese toxicity. Conclusions: Clinicians must be cognizant of the concentration of trace elements added to PN, as manganese, and perhaps other biometals, may accumulate when dosed above the recommended daily allowances.
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Affiliation(s)
- Justin P. Reinert
- Bon Secours Mercy Health St. Vincent Medical Center, Toledo, OH, USA
- The University of Texas at Tyler, TX, USA
| | - Laramie D. Forbes
- Bon Secours Mercy Health St. Vincent Medical Center, Toledo, OH, USA
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13
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Up-regulation of the manganese transporter SLC30A10 by hypoxia-inducible factors defines a homeostatic response to manganese toxicity. Proc Natl Acad Sci U S A 2021; 118:2107673118. [PMID: 34446561 DOI: 10.1073/pnas.2107673118] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Manganese (Mn) is an essential metal that induces incurable parkinsonism at elevated levels. However, unlike other essential metals, mechanisms that regulate mammalian Mn homeostasis are poorly understood, which has limited therapeutic development. Here, we discovered that the exposure of mice to a translationally relevant oral Mn regimen up-regulated expression of SLC30A10, a critical Mn efflux transporter, in the liver and intestines. Mechanistic studies in cell culture, including primary human hepatocytes, revealed that 1) elevated Mn transcriptionally up-regulated SLC30A10, 2) a hypoxia response element in the SLC30A10 promoter was necessary, 3) the transcriptional activities of hypoxia-inducible factor (HIF) 1 or HIF2 were required and sufficient for the SLC30A10 response, 4) elevated Mn activated HIF1/HIF2 by blocking the prolyl hydroxylation of HIF proteins necessary for their degradation, and 5) blocking the Mn-induced up-regulation of SLC30A10 increased intracellular Mn levels and enhanced Mn toxicity. Finally, prolyl hydroxylase inhibitors that stabilize HIF proteins and are in advanced clinical trials for other diseases reduced intracellular Mn levels and afforded cellular protection against Mn toxicity and also ameliorated the in vivo Mn-induced neuromotor deficits in mice. These findings define a fundamental homeostatic protective response to Mn toxicity-elevated Mn levels activate HIF1 and HIF2 to up-regulate SLC30A10, which in turn reduces cellular and organismal Mn levels, and further indicate that it may be possible to repurpose prolyl hydroxylase inhibitors for the management of Mn neurotoxicity.
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14
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Mulroy E, Baschieri F, Magrinelli F, Latorre A, Cortelli P, Bhatia KP. Movement Disorders and Liver Disease. Mov Disord Clin Pract 2021; 8:828-842. [PMID: 34401403 PMCID: PMC8354085 DOI: 10.1002/mdc3.13238] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/24/2021] [Accepted: 04/27/2021] [Indexed: 12/15/2022] Open
Abstract
The association of movement disorders with structural or functional hepatic disease occurs in three principal scenarios: (1) combined involvement of both organ systems from a single disease entity, (2) nervous system dysfunction resulting from exposure to toxic compounds in the setting of defective hepatic clearance, or (3) hepatic and/or neurological injury secondary to exposure to exogenous drugs or toxins. An important early step in the workup of any patient with combined movement disorders and liver disease is the exclusion of Wilson's disease. Diagnostic delay remains common for this treatable disorder, and this has major implications for patient outcomes. Thereafter, a structured approach integrating variables such as age of onset, tempo of progression, nature and severity of liver involvement, movement disorder phenomenology, exposure to drugs/toxins and laboratory/neuroimaging findings is key to ensuring timely diagnosis and disease‐specific therapy. Herein, we provide an overview of disorders which may manifest with a combination of movement disorders and liver disease, structured under the three headings as detailed above. In each section, the most common disorders are discussed, along with important clinical pearls, suggested diagnostic workup, differential diagnoses and where appropriate, treatment considerations.
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Affiliation(s)
- Eoin Mulroy
- Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London United Kingdom
| | - Francesca Baschieri
- IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.,Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italy
| | - Francesca Magrinelli
- Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London United Kingdom.,Department of Neurosciences Biomedicine and Movement Sciences, University of Verona Verona Italy
| | - Anna Latorre
- Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London United Kingdom
| | - Pietro Cortelli
- IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.,Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italy
| | - Kailash P Bhatia
- Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London United Kingdom
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15
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Ward LD, Tu HC, Quenneville CB, Tsour S, Flynn-Carroll AO, Parker MM, Deaton AM, Haslett PAJ, Lotta LA, Verweij N, Ferreira MAR, Baras A, Hinkle G, Nioi P. GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms. Nat Commun 2021; 12:4571. [PMID: 34315874 PMCID: PMC8316433 DOI: 10.1038/s41467-021-24563-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/23/2021] [Indexed: 02/07/2023] Open
Abstract
Understanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.
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Affiliation(s)
- Lucas D. Ward
- grid.417897.40000 0004 0506 3000Alnylam Pharmaceuticals, Cambridge, MA USA
| | - Ho-Chou Tu
- grid.417897.40000 0004 0506 3000Alnylam Pharmaceuticals, Cambridge, MA USA
| | | | - Shira Tsour
- grid.417897.40000 0004 0506 3000Alnylam Pharmaceuticals, Cambridge, MA USA
| | | | - Margaret M. Parker
- grid.417897.40000 0004 0506 3000Alnylam Pharmaceuticals, Cambridge, MA USA
| | - Aimee M. Deaton
- grid.417897.40000 0004 0506 3000Alnylam Pharmaceuticals, Cambridge, MA USA
| | | | - Luca A. Lotta
- grid.418961.30000 0004 0472 2713Regeneron Genetics Center, Tarrytown, NY USA
| | - Niek Verweij
- grid.418961.30000 0004 0472 2713Regeneron Genetics Center, Tarrytown, NY USA
| | | | | | | | - Aris Baras
- grid.418961.30000 0004 0472 2713Regeneron Genetics Center, Tarrytown, NY USA
| | - Gregory Hinkle
- grid.417897.40000 0004 0506 3000Alnylam Pharmaceuticals, Cambridge, MA USA
| | - Paul Nioi
- grid.417897.40000 0004 0506 3000Alnylam Pharmaceuticals, Cambridge, MA USA
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16
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Stracciari A, Spinardi L, Guarino M. Chronic acquired hepatocerebral degeneration presenting with Meige's syndrome and behavioral symptoms fully reversed by liver transplantation. Neurol Sci 2021; 42:4755-4758. [PMID: 34278516 DOI: 10.1007/s10072-021-05475-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/08/2021] [Indexed: 11/30/2022]
Abstract
Chronic acquired hepatocerebral degeneration (CAHD) is a rare neurologic syndrome occurring in patients with chronic liver disease, resulting in the combination of movement disorders and cognitive\behavioral changes. Its pathogenesis is debated and the symptoms are poorly responsive to medical therapy. Meige's syndrome is a form of cranial dystonia, considered an idiopathic form of adult onset dystonia. We report a 60-year-old man with HCV-related liver cirrhosis and hepatocarcinoma who developed Meige's syndrome associated with cognitive and behavioral manifestations, unrelated to acute metabolic derangement. CAHD was diagnosed. Liver transplantation reversed the clinical picture and MR abnormalities, reinforcing the idea that CAHD is a potentially reversible syndrome, which may be healed by liver transplantation and should not be considered a contraindication for this operation.
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Affiliation(s)
- Andrea Stracciari
- Neurology and Neuroradiology Units, S. Orsola-Malpighi University Hospital, IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
| | - Luca Spinardi
- Neurology and Neuroradiology Units, S. Orsola-Malpighi University Hospital, IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Maria Guarino
- Neurology and Neuroradiology Units, S. Orsola-Malpighi University Hospital, IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
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17
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Podymova SD. [New approaches to the pathogenesis, clinic, and treatment of hepatic encephalopathy]. TERAPEVT ARKH 2021; 93:236-242. [PMID: 36286643 DOI: 10.26442/00403660.2021.02.200613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 04/06/2021] [Indexed: 11/22/2022]
Abstract
This review article presents new approaches to the assessment of key pathogenesis factors, clinical features, and treatment of hepatic encephalopathy (HE) associated with liver cirrhosis. Various clinical variants of the course of HE in patients with cirrhosis of the liver areconsidered, which are important for the choice of treatment and prevention of repeated relapses of HE. Analyzed the ammonia hypothesis of pathogenesis and associated hyperammonemia, which is the basis of most modern treatment methods. These data on the activation of the adaptive pathway for removing ammonia in the form of glutamine are used in the further study of drugs that enhance the clearance of ammonia. The possibility of reducing GABA-ergic tone due to the effect of the antagonist on the neurosteroid site in the GABA receptor complex is emphasized.
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Affiliation(s)
- S D Podymova
- Loginov Moscow Clinical Research and Practical Center
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18
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Apetauerova D, Hildebrand P, Scala S, Zani JW, Lipert L, Clark E, Fennell T, Gordon FD. A Prospective Study of the Prevalence of Parkinsonism in Patients With Liver Cirrhosis. Hepatol Commun 2021; 5:323-333. [PMID: 33553978 PMCID: PMC7850299 DOI: 10.1002/hep4.1624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/02/2020] [Accepted: 09/12/2020] [Indexed: 02/04/2023] Open
Abstract
Acquired hepatocerebral degeneration refers to a neurological syndrome consisting of various movement disorders and cognitive impairment in advanced liver cirrhosis or portosystemic shunt. Neurological signs and symptoms may be attributed to the accumulation of toxic substances in the brain. The most common neurological presentation of this is parkinsonism. Our prospective study aimed to investigate the prevalence of parkinsonism in patients with cirrhosis who were evaluated for liver transplant and to identify any correlation between findings on brain magnetic resonance imaging (MRI) and severity of parkinsonism. Of the 120 enrolled participants with liver cirrhosis, 62 (52%) exhibited signs of parkinsonism and all had MRI basal ganglia hyperintensity. Eighteen patients from this group were transplanted and showed statistically significant improvements in their Unified Parkinson's Disease Rating Scale (UPDRS) scores. Conclusion: The data suggest the reversibility of the neurological impairment seen in cirrhosis, and therefore the effectiveness of transplantation in improving parkinsonian symptoms. There was no correlation between severity of MRI findings and clinical motor UPDRS part III. Laboratory findings showed no correlation among the abnormal levels, MRI brain signal abnormality, or UPDRS scores.
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Affiliation(s)
| | | | | | - Janet W Zani
- Lahey Hospital and Medical CenterBurlingtonMAUSA
| | | | - Erin Clark
- The University of New England College of Osteopathic MedicineBiddefordMEUSA
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19
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Kazi TG, Baloch S, Baig JA, Afridi HI, Arain MB. Evaluate the adverse impact of metal oxide on workers of different age groups that engage with gas metal arc welding process: health risk assessment. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:8652-8661. [PMID: 33064279 DOI: 10.1007/s11356-020-11192-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 10/07/2020] [Indexed: 06/11/2023]
Abstract
Immense epidemiological studies have been indicated about adverse effects of the welding fumes on the health of the welders, especially respiratory problems and other physiological disorders. The different types of welding mechanisms produce aerosols/fumes that contain different metals including chromium (Cr) and manganese (Mn). In the present study, the welders of two age groups (adolescents and adults) were selected; simultaneously the age-matched adolescents and adults belong to nonindustrial area as referents/control subjects. Biological samples (scalp hair) were collected from welders and referents, along with analyzed for Cr and Mn by electrothermal atomic absorption spectrometer, prior to acid digestion. To evaluate the occupational exposure on the health of the workers, the clinical features and biochemical parameters of selected population (exposed and non-exposed age-matched groups) were also carried out. The resulted data indicated that the concentrations of Mn and Cr were significantly higher in scalp hair samples of welders as compared to referent subjects (p < 0.01), verifying the absorption/exposure of both metals produced in welding fumes. The high prevalence of anemia and stomach disorder was observed in adolescent than adult welding workers. The incidence of asthma and related symptoms was elevated in adult welders than in younger boys. The neurological problems were particularly observed in aged welders > 50 years, might be due to long time exposure of welding fumes contains different toxicant especially Mn in ill ventilation system of workshops.
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Affiliation(s)
- Tasneem Gul Kazi
- National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080, Pakistan.
| | - Shahnawaz Baloch
- National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080, Pakistan
| | - Jameel Ahmed Baig
- National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080, Pakistan
| | - Hassan Imran Afridi
- National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080, Pakistan
| | - Mohammad Balal Arain
- National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080, Pakistan
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20
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Gentile F, Doneddu PE, Riva N, Nobile-Orazio E, Quattrini A. Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration. Int J Mol Sci 2020; 21:E7471. [PMID: 33050475 PMCID: PMC7590163 DOI: 10.3390/ijms21207471] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence gives support for the idea that extra-neuronal factors may affect brain physiology and its predisposition to neurodegenerative diseases. Epidemiological and experimental studies show that nutrition and metabolic disorders such as obesity and type 2 diabetes increase the risk of Alzheimer's and Parkinson's diseases after midlife, while the relationship with amyotrophic lateral sclerosis is uncertain, but suggests a protective effect of features of metabolic syndrome. The microbiota has recently emerged as a novel factor engaging strong interactions with neurons and glia, deeply affecting their function and behavior in these diseases. In particular, recent evidence suggested that gut microbes are involved in the seeding of prion-like proteins and their spreading to the central nervous system. Here, we present a comprehensive review of the impact of metabolism, diet and microbiota in neurodegeneration, by affecting simultaneously several aspects of health regarding energy metabolism, immune system and neuronal function. Advancing technologies may allow researchers in the future to improve investigations in these fields, allowing the buildup of population-based preventive interventions and development of targeted therapeutics to halt progressive neurologic disability.
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Affiliation(s)
- Francesco Gentile
- Experimental Neuropathology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy; (F.G.); (N.R.)
- Neuromuscular and Neuroimmunology Service, Humanitas Clinical and Research Institute IRCCS, 20089 Milan, Italy; (P.E.D.); (E.N.-O.)
| | - Pietro Emiliano Doneddu
- Neuromuscular and Neuroimmunology Service, Humanitas Clinical and Research Institute IRCCS, 20089 Milan, Italy; (P.E.D.); (E.N.-O.)
| | - Nilo Riva
- Experimental Neuropathology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy; (F.G.); (N.R.)
- Department of Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Eduardo Nobile-Orazio
- Neuromuscular and Neuroimmunology Service, Humanitas Clinical and Research Institute IRCCS, 20089 Milan, Italy; (P.E.D.); (E.N.-O.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy
| | - Angelo Quattrini
- Experimental Neuropathology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy; (F.G.); (N.R.)
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21
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Malaquias MJ, Pinto CM, Ramos C, Ferreira S, Gandara J, Almeida A, Cavaco S, Miranda HP, Magalhães M. Acquired hepatocerebral degeneration and hepatic encephalopathy: one or two entities? Eur J Neurol 2020; 27:2396-2404. [DOI: 10.1111/ene.14486] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/13/2020] [Indexed: 12/31/2022]
Affiliation(s)
- M. J. Malaquias
- Neurology Department Centro Hospitalar Universitário do Porto Porto Portugal
| | - C. M. Pinto
- Neuroradiology Department Centro Hospitalar Universitário do Porto Porto Portugal
| | - C. Ramos
- Neuroradiology Department Centro Hospitalar Universitário do Porto Porto Portugal
| | - S. Ferreira
- Hepatic Pancreatic Transplantation Unit Centro Hospitalar Universitário do Porto Porto Portugal
| | - J. Gandara
- Hepatic Pancreatic Transplantation Unit Centro Hospitalar Universitário do Porto Porto Portugal
| | - A. Almeida
- Chemistry Science Department Faculdade de Farmácia Universidade do Porto Porto Portugal
| | - S. Cavaco
- Neuropsychology Unit Centro Hospitalar Universitário do Porto Porto Portugal
| | - H. P. Miranda
- Hepatic Pancreatic Transplantation Unit Centro Hospitalar Universitário do Porto Porto Portugal
| | - M. Magalhães
- Neurology Department Centro Hospitalar Universitário do Porto Porto Portugal
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22
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Does Manganese Contribute to Methamphetamine-Induced Psychosis? CURRENT EMERGENCY AND HOSPITAL MEDICINE REPORTS 2020. [DOI: 10.1007/s40138-020-00221-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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23
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Taylor CA, Tuschl K, Nicolai MM, Bornhorst J, Gubert P, Varão AM, Aschner M, Smith DR, Mukhopadhyay S. Maintaining Translational Relevance in Animal Models of Manganese Neurotoxicity. J Nutr 2020; 150:1360-1369. [PMID: 32211802 PMCID: PMC7269748 DOI: 10.1093/jn/nxaa066] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/06/2020] [Accepted: 02/25/2020] [Indexed: 12/14/2022] Open
Abstract
Manganese is an essential metal, but elevated brain Mn concentrations produce a parkinsonian-like movement disorder in adults and fine motor, attentional, cognitive, and intellectual deficits in children. Human Mn neurotoxicity occurs owing to elevated exposure from occupational or environmental sources, defective excretion (e.g., due to cirrhosis), or loss-of-function mutations in the Mn transporters solute carrier family 30 member 10 or solute carrier family 39 member 14. Animal models are essential to study Mn neurotoxicity, but in order to be translationally relevant, such models should utilize environmentally relevant Mn exposure regimens that reproduce changes in brain Mn concentrations and neurological function evident in human patients. Here, we provide guidelines for Mn exposure in mice, rats, nematodes, and zebrafish so that brain Mn concentrations and neurobehavioral sequelae remain directly relatable to the human phenotype.
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Affiliation(s)
- Cherish A Taylor
- Division of Pharmacology & Toxicology, College of Pharmacy, Institute for Cellular & Molecular Biology, and Institute for Neuroscience, The University of Texas at Austin, Austin, TX, USA
| | - Karin Tuschl
- Department of Cell and Developmental Biology, University College London, London, United Kingdom,Department of Developmental Neurobiology, King's College London, London, United Kingdom,Address correspondence to KT (e-mail: )
| | - Merle M Nicolai
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Julia Bornhorst
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Priscila Gubert
- Department of Biochemistry, Laboratory of Immunopathology Keizo Asami-LIKA, Federal University of Pernambuco, Recife, Pernambuco, Brazil,Postgraduate Program in Pure and Applied Chemistry, Federal University of Western Bahia, Barreiras, Bahia, Brazil
| | - Alexandre M Varão
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Donald R Smith
- Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, CA, USA
| | - Somshuvra Mukhopadhyay
- Division of Pharmacology & Toxicology, College of Pharmacy, Institute for Cellular & Molecular Biology, and Institute for Neuroscience, The University of Texas at Austin, Austin, TX, USA,Address correspondence to SM (e-mail: )
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24
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Abstract
Hepatic encephalopathy (HE) is one of the major clinical decompensations of cirrhosis, with a high impact on health care resource utilization and cost. For an effective and comprehensive management of HE, the clinicians need to understand the pathophysiologic mechanisms of HE. This review describes the multiorgan processes involved in HE and how several HE precipitants and treatment strategies act on ammonia production, excretion, and neurotoxicity, including the impact of diabetes and use of cannabinoids. The authors also discuss the current and future role of gut microbiome, systemic/central inflammation, and various neurotransmitters for the pathogenesis and treatment of HE.
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Affiliation(s)
- Ariel Jaffe
- Section of Digestive Diseases, Yale Liver Center, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520-8019, USA
| | - Joseph K Lim
- Section of Digestive Diseases, Yale Liver Center, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520-8019, USA; VA Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Sofia Simona Jakab
- Section of Digestive Diseases, Yale Liver Center, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520-8019, USA; VA Connecticut Healthcare System, West Haven, Connecticut, USA.
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25
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Mercadante CJ, Prajapati M, Conboy HL, Dash ME, Herrera C, Pettiglio MA, Cintron-Rivera L, Salesky MA, Rao DB, Bartnikas TB. Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity. J Clin Invest 2019; 129:5442-5461. [PMID: 31527311 PMCID: PMC6877324 DOI: 10.1172/jci129710] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 09/10/2019] [Indexed: 12/30/2022] Open
Abstract
Manganese (Mn), an essential metal and nutrient, is toxic in excess. Toxicity classically results from inhalational exposures in individuals who work in industrial settings. The first known disease of inherited Mn excess, identified in 2012, is caused by mutations in the metal exporter SLC30A10 and is characterized by Mn excess, dystonia, cirrhosis, and polycythemia. To investigate the role of SLC30A10 in Mn homeostasis, we first generated whole-body Slc30a10-deficient mice, which developed severe Mn excess and impaired systemic and biliary Mn excretion. Slc30a10 localized to canalicular membranes of hepatocytes, but mice with liver Slc30a10 deficiency developed minimal Mn excess despite impaired biliary Mn excretion. Slc30a10 also localized to the apical membrane of enterocytes, but mice with Slc30a10 deficiency in small intestines developed minimal Mn excess despite impaired Mn export into the lumen of the small intestines. Finally, mice with Slc30a10 deficiency in liver and small intestines developed Mn excess that was less severe than that observed in mice with whole-body Slc30a10 deficiency, suggesting that additional sites of Slc30a10 expression contribute to Mn homeostasis. Overall, these results indicated that Slc30a10 is essential for Mn excretion by hepatocytes and enterocytes and could be an effective target for pharmacological intervention to treat Mn toxicity.
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Affiliation(s)
- Courtney J. Mercadante
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
| | - Milankumar Prajapati
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
| | - Heather L. Conboy
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
| | - Miriam E. Dash
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
| | - Carolina Herrera
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
| | - Michael A. Pettiglio
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
| | - Layra Cintron-Rivera
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
| | - Madeleine A. Salesky
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
| | - Deepa B. Rao
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Thomas B. Bartnikas
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
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How to approach a patient with parkinsonism - red flags for atypical parkinsonism. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2019; 149:1-34. [PMID: 31779810 DOI: 10.1016/bs.irn.2019.10.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Parkinsonism is a clinical syndrome defined by bradykinesia plus rigidity or tremor. Though most commonly encountered in the setting of idiopathic Parkinson's disease, a number of neurodegenerative, structural, metabolic and toxic neurological disorders can result in parkinsonism. Accurately diagnosing the underlying cause of parkinsonism is of both therapeutic and prognostic relevance, especially as we enter the era of disease-modifying treatment trials for neurodegenerative disorders. Being aware of the wide array of potential causes of parkinsonism is of paramount importance for clinicians. In this chapter, we present a pragmatic clinical approach to patients with parkinsonism, specifically focusing on 'red flags', which should alert one to consider diagnoses other than idiopathic Parkinson's disease.
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Abstract
Overt and covert hepatic encephalopathy (HE) are debilitating complications of cirrhosis. HE results in a poor quality of life for patients and their caregivers and, unless there is access to liver transplantation, the prognosis is poor. The development of overt HE is often unpredictable, and its management, particularly in the ward, remains challenging. There is an urgent need for novel approaches to treat HE. Until recently, therapies for this complication were disappointing, with frequently intolerable side effects such as diarrhoea and faecal incontinence. However, a non-absorbable antibiotic, rifaximin, * has been approved for the prevention of recurrent overt HE. It aims to reduce hospitalisation and resource use, as well as improve patients' quality of life. This article describes the practical aspects of diagnosing, classifying and managing HE. It reviews the pharmacological options for the treatment and prophylaxis of overt HE, and explores the evidence base demonstrating that rifaximin reduces the recurrence of overt HE.
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Affiliation(s)
- Debbie L Shawcross
- Reader and Honorary Consultant Hepatologist, Institute of Liver Studies, School of Immunity and Microbial Science, Faculty of Life Sciences and Medicine, King's College Hospital, London
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Ke T, Sidoryk-Wegrzynowicz M, Pajarillo E, Rizor A, Soares FAA, Lee E, Aschner M. Role of Astrocytes in Manganese Neurotoxicity Revisited. Neurochem Res 2019; 44:2449-2459. [PMID: 31571097 PMCID: PMC7757856 DOI: 10.1007/s11064-019-02881-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/13/2019] [Accepted: 09/16/2019] [Indexed: 12/17/2022]
Abstract
Manganese (Mn) overexposure is a public health concern due to its widespread industrial usage and the risk for environmental contamination. The clinical symptoms of Mn neurotoxicity, or manganism, share several pathological features of Parkinson's disease (PD). Biologically, Mn is an essential trace element, and Mn in the brain is preferentially localized in astrocytes. This review summarizes the role of astrocytes in Mn-induced neurotoxicity, specifically on the role of neurotransmitter recycling, neuroinflammation, and genetics. Mn overexposure can dysregulate astrocytic cycling of glutamine (Gln) and glutamate (Glu), which is the basis for Mn-induced excitotoxic neuronal injury. In addition, reactive astrocytes are important mediators of Mn-induced neuronal damage by potentiating neuroinflammation. Genetic studies, including those with Caenorhabditis elegans (C. elegans) have uncovered several genes associated with Mn neurotoxicity. Though we have yet to fully understand the role of astrocytes in the pathologic changes characteristic of manganism, significant strides have been made over the last two decades in deciphering the role of astrocytes in Mn-induced neurotoxicity and neurodegeneration.
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Affiliation(s)
- Tao Ke
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Marta Sidoryk-Wegrzynowicz
- Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Edward Pajarillo
- Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Asha Rizor
- Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Félix Alexandre Antunes Soares
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.,Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Eunsook Lee
- Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA. .,Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Room 209, Bronx, NY, 10461, USA.
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González-Regueiro J, la Tijera MHD, Moreno-Alcántar R, Torre A. Pathophysiology of hepatic encephalopathy and future treatment options. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2019. [DOI: 10.1016/j.rgmxen.2019.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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González-Regueiro JA, Higuera-de la Tijera MF, Moreno-Alcántar R, Torre A. Pathophysiology of hepatic encephalopathy and future treatment options. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2019; 84:195-203. [PMID: 31014748 DOI: 10.1016/j.rgmx.2019.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 01/28/2019] [Accepted: 02/18/2019] [Indexed: 06/09/2023]
Abstract
Understanding of the pathophysiology of hepatic encephalopathy has conditioned new treatment options. Ammonia detoxification in hepatic encephalopathy is regulated by two enzymes: glutaminase or glutamine synthetase. The first produces ammonia and the second detoxifies the ammonia, which is why treatments are aimed at glutaminase inhibition or glutamine synthetase activation. At present, we know that both enzymes are found not only in the liver, but also in the muscle, intestine, kidney, and brain. Therefore, current treatments can be directed at each enzyme at different sites. Awareness of those potential treatment sites makes different options of approach possible in the patient with hepatic encephalopathy, and each approach should be personalized.
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Affiliation(s)
- J A González-Regueiro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | | | - R Moreno-Alcántar
- Departamento de Gastroenterología, Centro Médico Nacional Siglo XXI, Ciudad de México, México
| | - A Torre
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México; Unidad de Hepatología y Trasplante Hepático, Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México.
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Abstract
Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, 'Parkinsonism in cirrhosis'. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.
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Affiliation(s)
- Roger F Butterworth
- Department of Medicine, University of Montreal, 45143 Cabot Trail, Englishtown, NS, B0C 1H0, Canada.
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Chen P, Totten M, Zhang Z, Bucinca H, Erikson K, Santamaría A, Bowma AB, Aschner M. Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment. Expert Rev Neurother 2019; 19:243-260. [PMID: 30759034 PMCID: PMC6422746 DOI: 10.1080/14737175.2019.1581608] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 02/08/2019] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Iron (Fe) and manganese (Mn) are essential nutrients for humans. They act as cofactors for a variety of enzymes. In the central nervous system (CNS), these two metals are involved in diverse neurological activities. Dyshomeostasis may interfere with the critical enzymatic activities, hence altering the neurophysiological status and resulting in neurological diseases. Areas covered: In this review, the authors cover the molecular mechanisms of Fe/Mn-induced toxicity and neurological diseases, as well as the diagnosis and potential treatment. Given that both Fe and Mn are abundant in the earth crust, nutritional deficiency is rare. In this review the authors focus on the neurological disorders associated with Mn and Fe overload. Expert commentary: Oxidative stress and mitochondrial dysfunction are the primary molecular mechanism that mediates Fe/Mn-induced neurotoxicity. Although increased Fe or Mn concentrations have been found in brain of patients, it remains controversial whether the elevated metal amounts are the primary cause or secondary consequence of neurological diseases. Currently, treatments are far from satisfactory, although chelation therapy can significantly decrease brain Fe and Mn levels. Studies to determine the primary cause and establish the molecular mechanism of toxicity may help to adapt more comprehensive and satisfactory treatments in the future.
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Affiliation(s)
- Pan Chen
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Melissa Totten
- Department of Nutrition, University of North Carolina Greensboro, Greensboro, NC, USA
| | - Ziyan Zhang
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Hana Bucinca
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Keith Erikson
- Department of Nutrition, University of North Carolina Greensboro, Greensboro, NC, USA
| | - Abel Santamaría
- Laboratory of Excitatory Amino Acids, National Institute of Neurology and Neurosurgery, Mexico, Mexico City, Mexico
| | - Aaron B. Bowma
- School of Health Sciences, Purdue University, West Lafayette, IN, USA
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
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Namazbaeva Z, Battakova S, Ibrayeva L, Sabirov Z. Change in metabolic and cognitive state among people of the Aral zone of ecological disaster. Isr J Ecol Evol 2018. [DOI: 10.1163/22244662-20181035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Risk factors in Aral Sea region include toxic metals that competitively interact with essential elements influencing their metabolism, affecting metabolic and cognitive functions. According to epidemiological data, cerebrovascular disease and thyroid function abnormality are the leading disorders. Cognitive and metabolic disorders are considered as risk factors in cerebrovascular diseases. Thus, the objective of current work was to determine the metabolic and cognitive state of people in Aralsk, associated with an imbalance of essential trace elements and find correlation between toxic metals load and psychoemotional status. 275 people between the ages of 21 and 45 years were involved. In evaluating cognitive state, a decrease in short-term memory for numbers and an increase in depression among subjects was found. An inverse correlation between the copper level in blood and short-term memory for numbers, between depression and iodine level in blood, between the zinc level in blood and the “attentional capacity” was also found. The results showed a significant metabolic stress among subjects during adaptation to a high chemical load. Data represent a cross-sectional age-dependent review of metabolic and cognitive processes and microelement metabolism among population, living in the Aral Sea region for a long time.
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Affiliation(s)
- Zulkiya Namazbaeva
- a Republican State Governmental Enterprise with the right of commercial activity “National Centre of Labour Hygiene and Occupational Diseases”, Ministry of Healthcare of the Republic of Kazakhstan, Karaganda, Kazakhstan
| | - Sharbanu Battakova
- a Republican State Governmental Enterprise with the right of commercial activity “National Centre of Labour Hygiene and Occupational Diseases”, Ministry of Healthcare of the Republic of Kazakhstan, Karaganda, Kazakhstan
| | - Lyazat Ibrayeva
- a Republican State Governmental Enterprise with the right of commercial activity “National Centre of Labour Hygiene and Occupational Diseases”, Ministry of Healthcare of the Republic of Kazakhstan, Karaganda, Kazakhstan
- b Republican State Governmental Enterprise with the right of commercial activity, Karaganda State Medical University, Ministry of Healthcare of the Republic of Kazakhstan, Karaganda, Kazakhstan
| | - Zhanbol Sabirov
- a Republican State Governmental Enterprise with the right of commercial activity “National Centre of Labour Hygiene and Occupational Diseases”, Ministry of Healthcare of the Republic of Kazakhstan, Karaganda, Kazakhstan
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Arenas A, Urzúa Á, Poniachik J, Carlos Diaz J, Castillo J, Saure A, Lembach H, Cancino A, Ibarra J, Besa C, Wolff R, Arrese M, Benítez C. Reversibility of Acquired Hepatocerebral Degeneration After Liver Transplantation. Liver Transpl 2018; 24:1133-1137. [PMID: 30142251 DOI: 10.1002/lt.25211] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 08/22/2016] [Accepted: 10/31/2016] [Indexed: 02/07/2023]
Affiliation(s)
- Alex Arenas
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Álvaro Urzúa
- Departamento de Medicina Interna, Sección de Gastroenterología
| | - Jaime Poniachik
- Departamento de Medicina Interna, Sección de Gastroenterología.,Unidad de Trasplante Hepático, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Juan Carlos Diaz
- Cirugía, Hospital Clínico Universidad de Chile, Santiago, Chile.,Unidad de Trasplante Hepático, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Jaime Castillo
- Cirugía, Hospital Clínico Universidad de Chile, Santiago, Chile.,Unidad de Trasplante Hepático, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Alexandre Saure
- Cirugía, Hospital Clínico Universidad de Chile, Santiago, Chile.,Unidad de Trasplante Hepático, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Hans Lembach
- Cirugía, Hospital Clínico Universidad de Chile, Santiago, Chile.,Unidad de Trasplante Hepático, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Alejandra Cancino
- Unidad de Trasplante Hepático, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - José Ibarra
- Unidad de Trasplante Hepático, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Cecilia Besa
- Radiología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rodrigo Wolff
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile.,Unidad de Trasplante Hepático, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile.,Unidad de Trasplante Hepático, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carlos Benítez
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile.,Unidad de Trasplante Hepático, Pontificia Universidad Católica de Chile, Santiago, Chile
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Atypical Neuropsychiatric Presentation in a Patient Expecting Liver Transplantation. Case Rep Transplant 2018; 2018:4609631. [PMID: 30112246 PMCID: PMC6077324 DOI: 10.1155/2018/4609631] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/15/2018] [Accepted: 05/20/2018] [Indexed: 01/17/2023] Open
Abstract
Patients presenting with acute or chronic hepatopathy can develop altered mental status with psychomotor slowing, most commonly indicating encephalopathy. We present the case of a 56-year-old patient who developed subacute atypical neuropsychiatric symptoms including cognitive and behavioural disorganization, manic-like state, and lateralized parkinsonian syndrome. The sequence of events, complete work-up, and detailed neuropsychiatric examination were not compatible with hepatic encephalopathy or delirium; therefore we extended our differential diagnosis and suggested the pathophysiological process described below.
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Ferreira MDF, Aylor AEA, Mellanby RJ, Campbell SM, Gow AG. Investigation of manganese homeostasis in dogs with anaemia and chronic enteropathy. Open Vet J 2018; 7:360-366. [PMID: 29296596 PMCID: PMC5738890 DOI: 10.4314/ovj.v7i4.12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 11/21/2017] [Indexed: 11/17/2022] Open
Abstract
Lethargy is a frequent and important clinical feature of anaemia; however, it does not absolutely correlate with the severity of anaemia. Manganese is efficiently absorbed through the gastrointestinal tract via divalent metal transporter 1 (DMT1), which is also responsible for iron transport. DMT1 is upregulated in iron deficiency (ID). Increased manganese concentrations are reported in ID anaemia (IDA) in various species. Manganese is neurotoxic and therefore may contribute to lethargy observed in some anaemic patients. In addition, anaemia and ID are common in human inflammatory bowel disease. Little is known about how anaemia influences manganese metabolism in veterinary patients and how common is anaemia in dogs with chronic enteropathy (CE). If elevated manganese concentrations are found, then potentially neurotoxicity may be contributing to morbidity in these cases. The objectives of this study were to investigate the hypothesis that whole blood manganese concentrations would be increased in dogs with anaemia, particularly in dogs with confirmed IDA, and that anaemia would be common in canine CE. Medical records from 2012-2016 were reviewed for dogs with CE that were anaemic, as well as dogs with confirmed IDA, where a sample suitable for manganese analysis was held in an archive. Manganese concentration was measured in whole blood from: 11 anaemic dogs with CE, 6 dogs with IDA, 9 non-anaemic ill controls, and 12 healthy controls. Mann-Whitney U and Kruskal-Wallis tests with post-test Dunn's multiple comparisons tests were performed, with P<0.05 considered significant. The prevalence of anaemia in canine CE was 20.6% (33/160). Manganese concentrations were significantly different between all groups (P=0.0001) and higher in non-anaemic than anaemic dogs (P=0.0078). Manganese concentrations were also higher in healthy compared to ill controls (P<0.0001), anaemic dogs with CE (P=0.0056) and to dogs with IDA (P=0.0001). No differences were observed between anaemic dogs with CE, IDA and ill controls. Although anaemia was frequently observed in canine CE, the hypothesis that dogs with anaemia would have increased manganese concentrations, possibly contributing to a lethargic state was not supported. Further research is warranted to understand the influence of anaemia on whole blood manganese.
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Affiliation(s)
- Marisa da Fonseca Ferreira
- Hospital for Small Animals, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, UK
| | | | - Richard John Mellanby
- Hospital for Small Animals, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, UK
| | - Susan Mary Campbell
- Hospital for Small Animals, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, UK
| | - Adam George Gow
- Hospital for Small Animals, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, UK
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Suárez I, Bodega G, Rubio M, Fernández B. Reduced TH expression and α-synuclein accumulation contribute towards nigrostriatal dysfunction in experimental hepatic encephalopathy. Restor Neurol Neurosci 2017; 35:469-481. [PMID: 28984618 DOI: 10.3233/rnn-170728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE The present work examines α-synuclein expression in the nigrostriatal system of a rat chronic hepatic encephalopathy model induced by portacaval anastomosis (PCA). There is evidence that dopaminergic dysfunction in disease conditions is strongly associated with such expression. Possible relationships among dopaminergic neurons, astroglial cells and α-synuclein expression were sought. METHODS Brain tissue samples from rats at 1 and 6 months post-PCA, and controls, were analysed immunohistochemically using antibodies against tyrosine hydroxylase (TH), α-synuclein, glial fibrillary acidic protein (GFAP) and ubiquitin (Ub). RESULTS In the control rats, TH immunoreactivity was detected in the neuronal cell bodies and processes in the substantia nigra pars compacta (SNc). A dense TH-positive network of neurons was also seen in the striatum. In the PCA-exposed rats, however, a reduction in TH-positive neurons was seen at both 1 and 6 months in the SNc, as well as a reduction in TH-positive fibres in the striatum. This was coincident with the appearance of α-synuclein-immunoreactive neurons in the SNc; some of the TH-positive neurons also showed α-synuclein immunoreactivity. In addition, α-synuclein accumulation was seen in the SNc and striatum at both 1 and 6 months post-PCA, whereas α-synuclein was only mildly expressed in the nigrostriatal pathway of the controls. Astrogliosis was also seen following PCA, as revealed by increased GFAP expression from 1 month to 6 months post-PCA in both the SN and striatum. The astroglial activation level in the SN paralleled the reduced neuronal expression of TH throughout PCA exposure. CONCLUSION α-synuclein accumulation following PCA may induce dopaminergic dysfunction via the downregulation of TH, as well as astroglial activation.
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Affiliation(s)
- Isabel Suárez
- Departamento de Biomedicina y Biotecnología, Universidad de Alcalá, Madrid, Spain
| | - Guillermo Bodega
- Departamento de Biomedicina y Biotecnología, Universidad de Alcalá, Madrid, Spain
| | - Miguel Rubio
- Departamento de Biomedicina y Biotecnología, Universidad de Alcalá, Madrid, Spain
| | - Benjamín Fernández
- Departamento de Biología Celular, Universidad Complutense, Madrid, Spain
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Jiao Y, Wang XH, Chen R, Tang TY, Zhu XQ, Teng GJ. Predictive models of minimal hepatic encephalopathy for cirrhotic patients based on large-scale brain intrinsic connectivity networks. Sci Rep 2017; 7:11512. [PMID: 28912425 PMCID: PMC5599725 DOI: 10.1038/s41598-017-11196-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 08/18/2017] [Indexed: 01/09/2023] Open
Abstract
We aimed to find the most representative connectivity patterns for minimal hepatic encephalopathy (MHE) using large-scale intrinsic connectivity networks (ICNs) and machine learning methods. Resting-state fMRI was administered to 33 cirrhotic patients with MHE and 43 cirrhotic patients without MHE (NMHE). The connectivity maps of 20 ICNs for each participant were obtained by dual regression. A Bayesian machine learning technique, called Graphical Model-based Multivariate Analysis, was applied to determine ICN regions that characterized group differences. The most representative ICNs were evaluated by the performance of three machine learning methods (support vector machines (SVMs), multilayer perceptrons (MLP), and C4.5). The clinical significance of these potential biomarkers was further tested. The temporal lobe network (TLN), and subcortical network (SCN), and sensorimotor network (SMN) were selected as representative ICNs. The distinct functional integration patterns of the representative ICNs were significantly correlated with behavior criteria and Child-Pugh scores. Our findings suggest the representative ICNs based on GAMMA can distinguish MHE from NMHE and provide supplementary information to current MHE diagnostic criteria.
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Affiliation(s)
- Yun Jiao
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China
| | - Xun-Heng Wang
- College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, 310018, China
| | - Rong Chen
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, School of Medicine, Baltimore, MD, 21201, USA
| | - Tian-Yu Tang
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China
| | - Xi-Qi Zhu
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.,Department of Radiology, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, 210003, China
| | - Gao-Jun Teng
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
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Shunt occlusion for portosystemic shunt syndrome related refractory hepatic encephalopathy-A single-center experience in 21 patients from Kerala. Indian J Gastroenterol 2017; 36:411-419. [PMID: 29124669 DOI: 10.1007/s12664-017-0787-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 09/08/2017] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Large spontaneous portosystemic shunts (SPSS) are seen in a subset of patients with liver disease and medically refractory recurrent/persistent hepatic encephalopathy (MRHE). Shunt occlusion has been shown to improve clinical outcomes. METHODS We retrospectively analyzed patient characteristics, SPSS attributes, procedural features, baseline clinical and investigational parameters, neurological outcomes, adverse effects (procedure and portal hypertension related), and risk factors predicting outcomes in liver disease patients undergoing shunt occlusion procedure for MRHE. RESULTS Between October 2016 and July 2017, 21 patients (Child-Pugh score, CTP 6 to 13) with mean model of end-stage liver disease (MELD) and MELD-sodium scores 15.7 and 19.3 respectively with MRHE [3-cirrhotic Parkinsonism (CP)] were diagnosed to have single or multiple large SPSSs. A total of 29 shunts were occluded (1 surgical, 20 non-surgical). Recurrent and persistent HE and CP markedly improved in the short (n=20, 1 to 3 months), intermediate (n=12, 3 to 6 months), and long (n=7, 6 to 9 months) follow up. None had spontaneous or persistent HE at a median follow up 105 (30 to 329) days (p<0.05). Motor, speech, sleep abnormalities, daily activities of living, and liver disease severity scores improved significantly on follow up. Baseline arterial ammonia showed a statistically significant reduction in all time periods of follow up after shunt occlusion (p<0.05). CTP >11 predicted mortality post shunt occlusion (p=0.04). Embolization of large SPSS in liver disease patients with MRHE and modestly preserved liver function is safe and efficacious and associated with improved quality of life and can function as a bridge to liver transplantation in accurately selected patients.
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Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis. PLoS Genet 2017; 13:e1006892. [PMID: 28692648 PMCID: PMC5524415 DOI: 10.1371/journal.pgen.1006892] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 07/24/2017] [Accepted: 06/23/2017] [Indexed: 12/28/2022] Open
Abstract
Recent studies found that mutations in the human SLC30A10 gene, which encodes a manganese (Mn) efflux transporter, are associated with hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC). However, the relationship between Mn metabolism and HMDPC is poorly understood, and no specific treatments are available for this disorder. Here, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system. Compared to wild-type animals, mutant adult animals developed significantly higher systemic Mn levels, and Mn accumulated in the brain and liver of mutant embryos in response to exogenous Mn. Interestingly, slc30a10 mutants developed neurological deficits in adulthood, as well as environmental Mn-induced manganism in the embryonic stage; moreover, mutant animals had impaired dopaminergic and GABAergic signaling. Finally, mutant animals developed steatosis, liver fibrosis, and polycythemia accompanied by increased epo expression. This phenotype was rescued partially by EDTA- CaNa2 chelation therapy and iron supplementation. Interestingly, prior to the onset of slc30a10 expression, expressing ATP2C1 (ATPase secretory pathway Ca2+ transporting 1) protected mutant embryos from Mn exposure, suggesting a compensatory role for Atp2c1 in the absence of Slc30a10. Notably, expressing either wild-type or mutant forms of SLC30A10 was sufficient to inhibit the effect of ATP2C1 in response to Mn challenge in both zebrafish embryos and HeLa cells. These findings suggest that either activating ATP2C1 or restoring the Mn-induced trafficking of ATP2C1 can reduce Mn accumulation, providing a possible target for treating HMDPC. Impaired function of the manganese transporter SLC30A10 has been implicated in HMDPC (hypermanganesemia with dystonia, polycythemia, and cirrhosis), an early-onset metabolic disorder clinically characterized by increased systemic Mn levels, neurological impairment, polycythemia, and hepatic injury. No specific treatment is currently available for HMDPC. Moreover, the mechanisms that underlie Mn metabolism are poorly understood, thereby hindering the development of effective treatments. To investigate the physiological processes underlying Mn metabolism and to develop new disease models of HMDPC, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system and found that these mutants develop clinical deficits typically associated with HMDPC. Furthermore, we identified a putative compensatory role for ATP2C1 in the absence of SLC30A10 with respect to modulating Mn metabolism. These findings provide a valuable tool for investigating the role of manganese dysregulation in neurological degenerative diseases and which can be used to develop new pharmacological approaches for managing Mn accumulation.
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Feltracco P, Cagnin A, Carollo C, Barbieri S, Ori C. Neurological disorders in liver transplant candidates: Pathophysiology and clinical assessment. Transplant Rev (Orlando) 2017; 31:193-206. [DOI: 10.1016/j.trre.2017.02.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 12/29/2016] [Accepted: 02/20/2017] [Indexed: 12/14/2022]
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Ishii N, Mochizuki H, Sakai K, Shiomi K, Nakazato M. Parkinsonism and high-intensity midbrain lesions on T2-weighted imaging in hepatic encephalopathy: a case report. Neurol Sci 2017; 38:1547-1549. [PMID: 28451765 DOI: 10.1007/s10072-017-2976-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Accepted: 04/19/2017] [Indexed: 10/19/2022]
Affiliation(s)
- Nobuyuki Ishii
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
| | - Hitoshi Mochizuki
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.
| | - Katsuya Sakai
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
| | - Kazutaka Shiomi
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
| | - Masamitsu Nakazato
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
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Yang HJ, Park SH, Seo M, Weon YC, Kim Y. 18F-FP-CIT dopamine transporter PET findings in cirrhotic patients with parkinsonism. Neurotoxicology 2017; 64:78-84. [PMID: 28259768 DOI: 10.1016/j.neuro.2017.02.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 02/28/2017] [Accepted: 02/28/2017] [Indexed: 02/07/2023]
Abstract
We report the clinical features and imaging findings of presynaptic dopamine transporter (DAT) positron emission tomography (PET) in four of patients with liver cirrhosis and concurrent parkinsonism. We also reviewed previously reported cases of cirrhosis-related parkinsonism using dopaminergic molecular imaging. Our results using 18F-radiolabeled N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) DAT PET in four patients with cirrhosis and parkinsonism showed two different molecular imaging patterns well related to their neurological symptoms. 18F-FP-CIT PET imaging of two patients showed normal DAT density in the striatum. Their clinical features included symmetric parkinsonism, early gait disturbances and postural instability, and the absence of resting tremor. The other two patients showed reduced striatal DAT uptake asymmetrically with a rostrocaudal gradient similar to idiopathic Parkinson's disease (IPD). They had clinical findings of hemiparkinsonism, resting tremor, without early gait disturbance or postural instability. They also showed sustained response to levodopa treatment. Based on the structured review of 21 cases with cirrhosis-related parkinsonism in the literature including the present cases, we categorized cirrhotic parkinsonism into three groups. Eleven of the twenty-one cases were categorized into group 1; levodopa-resistant atypical parkinsonism without a dopaminergic deficit in molecular imaging similar to primary manganism. Another 6 cases were categorized into group 2; coincidental IPD with superimposed cirrhosis with sustained good response to levodopa and presynaptic dopaminergic deficit with rostrocaudal gradient typical of IPD. The other undetermined 4 cases were categorized into group 3. They showed symmetric parkinsonism with variable response to levodopa therapy. Their molecular imaging showed a global diffuse dopaminergic deficit in the presynaptic molecular imaging distinct to group 1 (normal uptake) or 2 (asymmetric rostrocaudal deficit). In conclusion, cirrhosis-related parkinsonism is a heterogeneous disorder.
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Affiliation(s)
- Hui-Jun Yang
- Department of Neurology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
| | - Seol Hoon Park
- Department of Nuclear Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
| | - Minjung Seo
- Department of Nuclear Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
| | - Young Cheol Weon
- Department of Radiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
| | - Yangho Kim
- Department of Occupational and Environmental Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Bangeojinsunhwan-doro, Dong-gu, Ulsan 44033, South Korea.
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Abstract
Health-related quality of life (HRQOL) has become an important outcome for patients with liver cirrhosis as the number of transplantation candidates increases by the progression of treatment strategies. Falls and fall-related injuries are common in patients with liver cirrhosis and negatively affect HRQOL. Many factors increase the risk for falls such as minimal hepatic encephalopathy, psychoactive drugs, muscle strength, autonomic dysfunction, hyponatremia, and sleep problems. It is important to understand the underlying mechanisms for falls in cirrhotic patients to prevent severe injuries such as fractures, decrease healthcare costs, and improve HRQOL. Healthcare professionals, including physiotherapists and nurses, should be aware of the higher risk for falls in this population and therapeutic interventions must be designed for patients, especially those waiting on the transplant list.
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Shin HW, Park HK. Recent Updates on Acquired Hepatocerebral Degeneration. Tremor Other Hyperkinet Mov (N Y) 2017; 7:463. [PMID: 28975044 PMCID: PMC5623760 DOI: 10.7916/d8tb1k44] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 07/24/2017] [Indexed: 04/21/2023] Open
Abstract
BACKGROUND Acquired hepatocerebral degeneration (AHD) refers to a chronic neurological syndrome in patients with advanced hepatobiliary diseases. This comprehensive review focuses on the pathomechanism and neuroimaging findings in AHD. METHODS A PubMed search was performed using the terms "acquired hepatocerebral degeneration," "chronic hepatocerebral degeneration," "Non-Wilsonian hepatocerebral degeneration," "cirrhosis-related parkinsonism," and "manganese and liver disease." RESULTS Multiple mechanisms involving the accumulation of toxic substances such as ammonia or manganese and neuroinflammation may lead to widespread neurodegeneration in AHD. Clinical characteristics include movement disorders, mainly parkinsonism and ataxia-plus syndrome, as well as cognitive impairment with psychiatric features. Neuroimaging studies of AHD with parkinsonism show hyperintensity in the bilateral globus pallidus on T1-weighted magnetic resonance images, whereas molecular imaging of the presynaptic dopaminergic system shows variable findings. Ataxia-plus syndrome in AHD may demonstrate high-signal lesions in the middle cerebellar peduncles on T2-weighted images. DISCUSSION Future studies are needed to elucidate the exact pathomechanism and neuroimaging findings of this heterogeneous syndrome.
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Affiliation(s)
- Hae-Won Shin
- Department of Neurology, Chung-Ang University College of Medicine, Seoul, Republic of Korea
- Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, USA
| | - Hee Kyung Park
- Department of Neurology, Inje University Ilsan-Paik Hospital, Goyang, Republic of Korea
- Movement Disorder Center, Department of Neurosciences, University of California San Diego, San Diego, CA, USA
- *To whom correspondence should be addressed. E-mail:
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Butterworth RF. Pathogenesis of hepatic encephalopathy in cirrhosis: the concept of synergism revisited. Metab Brain Dis 2016; 31:1211-1215. [PMID: 26521983 DOI: 10.1007/s11011-015-9746-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 10/05/2015] [Indexed: 01/31/2023]
Abstract
The concept of synergistic mechanisms as the pathophysiologic basis of hepatic encephalopathy started with the pioneering work of Les Zieve in Minneapolis some 60 years ago where synergistic actions of the liver-derived toxins ammonia, methanethiol, and octanoic acid were described. More recently, synergistic actions of ammonia and manganese, a toxic metal that is normally eliminated via the hepatobiliary route and shown to accumulate in brain in liver failure, on the glutamatergic neurotransmitter system were described. The current upsurge of interest in brain inflammation (neuroinflammation) in relation to the CNS complications of liver failure has added a third dimension to the synergy debate. The combined actions of ammonia, manganese and pro-inflammatory cytokines in brain in liver failure result in oxidative/nitrosative stress resulting from activation of glutamate (NMDA) receptors and consequent nitration of key brain proteins. One such protein, glutamine synthetase, the sole enzyme responsible for brain ammonia removal is nitrated and inactivated in brain in liver failure. Consequently, brain ammonia levels increase disproportionately resulting in alterations of brain excitability, impaired brain energy metabolism, encephalopathy and brain swelling. Experimental therapeutic approaches for which proof-of-principle has been established include the NMDA receptor antagonist memantine, N-acetyl cysteine (recently shown to have antioxidant properties at both hepatic and cerebral levels) and probiotics.
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Affiliation(s)
- Roger F Butterworth
- Department of Medicine, University of Montreal, 45143 Cabot Trail, Englishtown, NS, B0C 1H0, Canada.
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Ganapathy D, Bajaj JS. Neurological examination. Clin Liver Dis (Hoboken) 2016; 7:151-153. [PMID: 31041051 PMCID: PMC6490279 DOI: 10.1002/cld.558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 04/27/2016] [Indexed: 02/04/2023] Open
Affiliation(s)
- Dinesh Ganapathy
- Division of Gastroenterology, Hepatology and NutritionVirginia Commonwealth University and McGuire VA Medical CenterRichmondVA
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology and NutritionVirginia Commonwealth University and McGuire VA Medical CenterRichmondVA
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Abstract
OPINION STATEMENT Liver disease, both in its acute and chronic forms, can be associated with a wide spectrum of neurologic manifestations, both central and peripheral, ranging in severity from subclinical changes to neurocritical conditions. Neurologists are frequently consulted to participate in their management. In this review, we present an overview of management strategies for patients with hepatic disease whose clinical course is complicated by neurologic manifestations. Type A hepatic encephalopathy (HE), which occurs in acute liver failure, is a neurologic emergency, and multiple measures should be taken to prevent and treat cerebral edema. In Type C HE, which occurs in chronic liver disease, management should be aimed at correcting precipitant factors and hyperammonemia. There is an increasing spectrum of drug treatments available to minimize ammonia toxicity. Acquired hepatocerebral degeneration is a rare complication of the chronic form of HE, with typical clinical and brain MRI findings, whose most effective treatment is liver transplantation. Epilepsy is frequent and of multifactorial cause in patients with hepatic disease, and careful considerations should be made regarding choice of the appropriate anti-epileptic drugs. Several mechanisms increase the risk of stroke in hepatic disease, but many of the drugs used to treat and prevent stroke are contraindicated in severe hepatic failure. Hepatitis C infection increases the risk of ischemic stroke. Hemorrhagic stroke is more frequent in patients with liver disease of alcoholic etiology. Viral hepatitis is associated with a wide range of immune-mediated complications, mostly in the peripheral nervous system, which respond to different types of immunomodulatory treatment. Several drugs used to treat hepatic disease, such as the classical and the new direct-acting antivirals, may have neurologic complications which in some cases preclude its continued use.
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Guilarte TR, Gonzales KK. Manganese-Induced Parkinsonism Is Not Idiopathic Parkinson's Disease: Environmental and Genetic Evidence. Toxicol Sci 2016. [PMID: 26220508 DOI: 10.1093/toxsci/kfv099] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Movement abnormalities caused by chronic manganese (Mn) intoxication clinically resemble but are not identical to those in idiopathic Parkinson's disease. In fact, the most successful parkinsonian drug treatment, the dopamine precursor levodopa, is ineffective in alleviating Mn-induced motor symptoms, implying that parkinsonism in Mn-exposed individuals may not be linked to midbrain dopaminergic neuron cell loss. Over the last decade, supporting evidence from human and nonhuman primates has emerged that Mn-induced parkinsonism partially results from damage to basal ganglia nuclei of the striatal "direct pathway" (ie, the caudate/putamen, internal globus pallidus, and substantia nigra pars reticulata) and a marked inhibition of striatal dopamine release in the absence of nigrostriatal dopamine terminal degeneration. Recent neuroimaging studies have revealed similar findings in a particular group of young drug users intravenously injecting the Mn-containing psychostimulant ephedron and in individuals with inherited mutations of the Mn transporter gene SLC30A10. This review will provide a detailed discussion about the aforementioned studies, followed by a comparison with their rodent analogs and idiopathic parkinsonism. Together, these findings in combination with a limited knowledge about the underlying neuropathology of Mn-induced parkinsonism strongly support the need for a more complete understanding of the neurotoxic effects of Mn on basal ganglia function to uncover the appropriate cellular and molecular therapeutic targets for this disorder.
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Affiliation(s)
- Tomás R Guilarte
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032
| | - Kalynda K Gonzales
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032
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Ototoxicity of Divalent Metals. Neurotox Res 2016; 30:268-82. [DOI: 10.1007/s12640-016-9627-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 04/21/2016] [Accepted: 04/22/2016] [Indexed: 12/16/2022]
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