|
1
|
Suktas A, Ekalaksananan T, Aromseree S, Bumrungthai S, Songserm N, Pientong C. Genetic polymorphism involved in major depressive disorder: a systemic review and meta-analysis. BMC Psychiatry 2024; 24:716. [PMID: 39438912 PMCID: PMC11515766 DOI: 10.1186/s12888-024-06195-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Genetic polymorphism studies in families and twins indicated the heritability of depression. However, the association between genes with genetic polymorphism and depression provides various findings and remains unclear. Therefore, we conducted a systematic review and meta-analysis to determine the genes with their polymorphism associated with the symptomatic depression known as major depressive disorder (MDD). MATERIALS AND METHODS PubMed and Scopus were searched for relevant studies published before May 22, 2023 (1968-2023), and 62 were selected for this review. The study's bias risk was investigated using the Newcastle-Ottawa scale. Gene functional enrichment analysis was investigated for molecular function (MF) and biological process (BP) and pathways. A meta-analysis of the studied genes that were replicative in the same single nucleotide polymorphism was conducted using a random-effect model. RESULTS The 49 genes involved in MDD were studied and engaged in several pathways, such as tryptophan metabolism or dopaminergic and serotonergic synapses. Based on gene overlapping in MF and BP, 13 genes with polymorphisms were identified as related to MDD. Most of them were only studied once. Solute carrier family 6 member 4 (SLC6A4) overlapping between MF and BP and brain-derived neurotrophic factor (BDNF) as unique to BP were replicative studied and used in the meta-analysis. The polymorphism of SLC6A4 SS and LS genotypes increased the occurrence of MDD development but not significantly [odd ratio (OR) = 1.39; 95% confidence interval (CI) = 0.87-2.22; P = 0.16 and OR = 1.13; 95% CI = 0.84-1.53; P = 0.42, respectively]. A similar result was observed for BDNF rs6265 GG (OR = 1.26; 95% CI = 0.78-2.06; P = 0.35) and BDNF rs6265 AA genotypes (OR = 1.12; 95% CI = 0.77-1.64; P = 0.56). These studies indicated low bias and significant heterogeneity. CONCLUSION At least 13 studied genes with polymorphisms were involved in MDD development according to MF and BP, but not significantly. These results suggest that MDD development risk factors might require genetic and other factors for interaction and induction.
Collapse
Grants
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
Collapse
Affiliation(s)
- Areeya Suktas
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Tipaya Ekalaksananan
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sirinart Aromseree
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sureewan Bumrungthai
- Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand
| | - Nopparat Songserm
- Faculty of Public Health, Ubon Ratchathani Rajabhat University, Ubon Ratchathani, Thailand
| | - Chamsai Pientong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
| |
Collapse
|
|
2
|
Balakrishnan B, Arul SS, Ravindran A, Venkataraman S. Brain Virome in Neurodegenerative Disorders: Insights from Transcriptomic Data Analysis. ACS Chem Neurosci 2023; 14:3979-3985. [PMID: 37812144 DOI: 10.1021/acschemneuro.3c00432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2023] Open
Abstract
Neurodegenerative disorders (NDs) are chronic ailments of the central nervous system that gradually deteriorate the structures and functions of neurons. The etiologies of NDs include genetic factors, aging, infections, starvation, brain trauma, and spinal cord injury, among others. However, it is unclear whether viral infections impact the prognosis of NDs or contribute to their development. Hence, we investigated the prevalence of neurotropic viruses in brain samples by using transcriptomic data. A total of 1635 viral isolates with complete genomic information was used to investigate the incidence of 18 distinct viruses across 129 data sets from healthy and ND subjects. Our findings support the evidence pointing to the existence of a brain virome where certain viruses co-occur. We further hypothesize that distinct virome profiles are linked to different forms of NDs.
Collapse
Affiliation(s)
| | | | - Aarti Ravindran
- Department of Biotechnology, Anna University, Chennai 600025, India
| | | |
Collapse
|
|
3
|
Schmidt J, Cruz M, Tolentino J, Carmo A, Paes M, de Lacerda G, Gjorup A, Schmidt S. COVID-19 Patients with Early Gastrointestinal Symptoms Show Persistent Deficits in Specific Attention Subdomains. J Clin Med 2023; 12:jcm12051931. [PMID: 36902717 PMCID: PMC10003448 DOI: 10.3390/jcm12051931] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/17/2023] [Accepted: 02/27/2023] [Indexed: 03/05/2023] Open
Abstract
Previous studies have shown that COVID-19 inpatients exhibited significant attentional deficits on the day of discharge. However, the presence of gastrointestinal symptoms (GIS) has not been evaluated. Here, we aimed to verify: (1) whether COVID-19 patients with GIS exhibited specific attention deficits; (2) which attention subdomain deficits discriminated patients with GIS and without gastrointestinal symptoms (NGIS) from healthy controls. On admission, the presence of GIS was recorded. Seventy-four physically functional COVID-19 inpatients at discharge and sixty-eight controls underwent a Go/No-go computerized visual attentional test (CVAT). A Multivariate Analysis of Covariance (MANCOVA) was performed to examine group differences in attentional performance. To discriminate which attention subdomain deficits discriminated GIS and NGIS COVID-19 patients from healthy controls, a discriminant analysis was applied using the CVAT variables. The MANCOVA showed a significant overall effect of COVID-19 with GIS on attention performance. The discriminant analysis indicated that the GIS group could be differentiated from the controls by variability of reaction time and omissions errors. The NGIS group could be differentiated from controls by reaction time. Late attention deficits in COVID-19 patients with GIS may reflect a primary problem in the sustained and focused attention subsystems, whereas in NGIS patients the attention problems are related to the intrinsic-alertness subsystem.
Collapse
Affiliation(s)
- Juliana Schmidt
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Maria Cruz
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Julio Tolentino
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Aureo Carmo
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Maria Paes
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Glenda de Lacerda
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Ana Gjorup
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| | - Sergio Schmidt
- Postgraduate Neurology Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 202709001, Brazil
| |
Collapse
|
|
4
|
Buawangpong N, Pinyopornpanish K, Phinyo P, Jiraporncharoen W, Angkurawaranon C, Soontornpun A. Effect of Comorbidities on Ten-Year Survival in Patients with Dementia. J Alzheimers Dis 2023; 94:163-175. [PMID: 37212105 DOI: 10.3233/jad-221259] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
BACKGROUND There is a verified association between comorbidity and survival in patients with dementia. OBJECTIVE To describe the ten-year survival probability of patients with dementia and to identify the impact of comorbidity. METHODS The prognostic retrospective cohort study was conducted using data from adults with dementia who had visited the outpatient departments at Maharaj Nakorn Chiang Mai hospital between 2006 and 2012. Dementia was verified in accordance with standard practice guidelines. Secondary data detailing about patient age, gender, date of dementia diagnosis and death, types of dementia, and comorbidities at the time of dementia diagnosis was obtained from electronic medical records. The association between comorbidity, patients' underlying disease at dementia diagnosis, and overall survival were analyzed using a multivariable Cox proportional hazard model adjusted for age, gender, types of dementia, and other comorbidities. RESULTS Of the 702 patients, 56.9% were female. Alzheimer's disease (39.6%) was the most prevalent type of dementia. Median overall survival was 6.0 years (95% CI 5.5- 6.7). The comorbidities associated with a high risk of mortality included liver disease (aHR 2.70, 95% CI 1.46- 5.00), atrial fibrillation (aHR 2.15, 95% CI 1.29- 3.58), myocardial infarction (aHR 1.55, 95% CI 1.07- 2.26), and type 2 diabetes mellitus (aHR 1.40, 95% CI 1.13- 1.74). CONCLUSION Overall survival rate of patients with dementia in Thailand was comparable to previous studies. Several comorbidities were associated with a ten-year survival. The prognosis of patients with dementia may be improved by appropriate care of comorbidities.
Collapse
Affiliation(s)
- Nida Buawangpong
- Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Global Health and Chronic Conditions Research Group, Chiang Mai University, Chiang Mai, Thailand
| | - Kanokporn Pinyopornpanish
- Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Global Health and Chronic Conditions Research Group, Chiang Mai University, Chiang Mai, Thailand
| | - Phichayut Phinyo
- Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center for Clinical Epidemiology and Clinical Statistics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Musculoskeletal Science and Translational Research (MSTR), Chiang Mai University, Chiang Mai, Thailand
| | - Wichuda Jiraporncharoen
- Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Global Health and Chronic Conditions Research Group, Chiang Mai University, Chiang Mai, Thailand
| | - Chaisiri Angkurawaranon
- Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Global Health and Chronic Conditions Research Group, Chiang Mai University, Chiang Mai, Thailand
| | - Atiwat Soontornpun
- Department of Internal Medicine, Division of Neurology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| |
Collapse
|
|
5
|
Shehata GA, Ahmed GK, Hassan EA, Rehim ASEDA, Mahmoud SZ, Masoud NA, Seifeldein GS, Hassan WA, Aboshaera KO. Impact of direct-acting antivirals on neuropsychiatric and neurocognitive dysfunction in chronic hepatitis C patients. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2022. [DOI: 10.1186/s41983-022-00568-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Abstract
Background
Hepatitis C virus (HCV) infection is associated with psychiatric and cognitive dysfunctions. We aimed to investigate depression, anxiety, and cognitive function of chronic hepatitis C (CHC) patients before and after treatment with direct-acting antivirals (DAAs). Forty CHC patients (20 non-cirrhotic and 20 cirrhotic) who had undergone DAA treatment in our outpatient clinic and ten controls. We administered the Hospital Anxiety and Depression questionnaires to measure the anxiety and depression symptoms and the Cognitive Abilities Screening Instruments (CASI) to measure the cognitive function at the beginning and 3 months after the end of the treatment.
Results
Sustained virological response (SVR) was achieved in all patients. Post-treatment anxiety and depression scores showed a significant improvement than pre-treatment ones in CHC patients. Regarding CASI, before and after the treatment, a statistical significance was found in short-term memory (P = 0.001), concentration (P = 0.033), abstract thinking and judgment (P = 0.024), total (P = 0.001) in non-cirrhotic, Also, an improvement was seen in long-term memory (P = 0.015), short-term memory (P < 0.001), concentration (P = 0.024) and total (P = 0.01) in cirrhotic. However, these changes were still impaired in post-treated cirrhotic compared to controls.
Conclusions
CHC patients' anxiety, depression, and cognitive function partially improved after DAA therapy. Besides, improving the status of CHC, reversibility of cognitive dysfunction in non-cirrhotic patients may indicate the importance of treatment in early stages of liver disease.
Collapse
|
|
6
|
Wang M, Huang P, Liu W, Tan W, Chen T, Zeng T, Zhu C, Shao J, Xue H, Li J, Yue M. Risk factors of severe fever with thrombocytopenia syndrome combined with central neurological complications: A five-year retrospective case-control study. Front Microbiol 2022; 13:1033946. [PMID: 36406394 PMCID: PMC9668900 DOI: 10.3389/fmicb.2022.1033946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/17/2022] [Indexed: 10/31/2023] Open
Abstract
OBJECTIVE Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality rate, especially SFTS combined with central neurological complications. The purpose of this study was to explore risk factors of central neurological complications in SFTS patients. METHODS In this retrospective study, SFTS patients admitted to the First Affiliated Hospital of Nanjing Medical University between January 2017 and December 2021 were enrolled. Based on the presence or absence of central neurological complications, SFTS patients were divided into case group and control group. The patients' laboratory parameters and clinical data were collected for statistical analysis. Receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction accuracy of independent risk factors in identifying SFTS patients with central neurological complications. RESULTS In total, 198 hospitalized SFTS patients with complete medical records, clear etiological diagnosis and clinical outcomes were enrolled in this study. Of these, 74 (37.4%) cases were diagnosed with SFTS with central neurological complications, 29 (39.2%) cases died, and no death occurred in the control group. Multivariate logistic regression analysis revealed pulmonary rales, atrial fibrillation, and high serum SFTSV RNA, lactate dehydrogenase level during the fever stage as independent risk factors for the development of central neurological complications in SFTS patients. ROC curve analysis showed that the area under the ROC curve (AUC) of serum SFTSV RNA and lactate dehydrogenase levels were 0.748 (95%CI: 0.673-0.823, p < 0.001) and 0.864 (95%CI: 0.815-0.914, p < 0.001), respectively, in central neurological complications predicted in SFTS patients. CONCLUSION Severe fever with thrombocytopenia syndrome (SFTS) combined with central neurological complications has high morbidity and mortality and diverse clinical manifestations. Early monitoring of lung signs, electrocardiogram, blood SFTSV RNA, and lactate dehydrogenase levels in SFTS patients may be useful in predicting the occurrence of central neurological complications.
Collapse
Affiliation(s)
- Min Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Peng Huang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wei Liu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- State Key Lab Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Weilong Tan
- Department of Infectious Disease Prevention and Control, Eastern Theater Command Centers for Disease Control and Prevention, Nanjing, China
| | - Tianyan Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tian Zeng
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chuanlong Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department Infectious and Tropical Diseases, The Second Affiliation Hospital of Hainan Medical University, Haikou, China
| | - Jianguo Shao
- Department of Gastroenterology, Nantong Third People’s Hospital Affiliated to Nantong University, Nantong, China
| | - Hong Xue
- Department of Hepatology, Nantong Third People’s Hospital Affiliated to Nantong University, Nantong, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ming Yue
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
7
|
Nebie O, Buée L, Blum D, Burnouf T. Can the administration of platelet lysates to the brain help treat neurological disorders? Cell Mol Life Sci 2022; 79:379. [PMID: 35750991 PMCID: PMC9243829 DOI: 10.1007/s00018-022-04397-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 05/09/2022] [Accepted: 05/23/2022] [Indexed: 11/03/2022]
Abstract
Neurodegenerative disorders of the central nervous system (CNS) and brain traumatic insults are characterized by complex overlapping pathophysiological alterations encompassing neuroinflammation, alterations of synaptic functions, oxidative stress, and progressive neurodegeneration that eventually lead to irreversible motor and cognitive dysfunctions. A single pharmacological approach is unlikely to provide a complementary set of molecular therapeutic actions suitable to resolve these complex pathologies. Recent preclinical data are providing evidence-based scientific rationales to support biotherapies based on administering neurotrophic factors and extracellular vesicles present in the lysates of human platelets collected from healthy donors to the brain. Here, we present the most recent findings on the composition of the platelet proteome that can activate complementary signaling pathways in vivo to trigger neuroprotection, synapse protection, anti-inflammation, antioxidation, and neurorestoration. We also report experimental data where the administration of human platelet lysates (HPL) was safe and resulted in beneficial neuroprotective effects in established rodent models of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, traumatic brain injury, and stroke. Platelet-based biotherapies, prepared from collected platelet concentrates (PC), are emerging as a novel pragmatic and accessible translational therapeutic strategy for treating neurological diseases. Based on this assumption, we further elaborated on various clinical, manufacturing, and regulatory issues that need to be addressed to ensure the ethical supply, quality, and safety of HPL preparations for treating neurodegenerative and traumatic pathologies of the CNS. HPL made from PC may become a unique approach for scientifically based treatments of neurological disorders readily accessible in low-, middle-, and high-income countries.
Collapse
Affiliation(s)
- Ouada Nebie
- College of Biomedical Engineering, Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, 250 Wu-Xing Street, Taipei, 11031, Taiwan
- University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience and Cognition, 59045, Lille, France
- Alzheimer and Tauopathies, LabEx DISTALZ, LiCEND, 59000, Lille, France
| | - Luc Buée
- University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience and Cognition, 59045, Lille, France
- Alzheimer and Tauopathies, LabEx DISTALZ, LiCEND, 59000, Lille, France
- NeuroTMULille International Laboratory, Univ. Lille, Lille, France
| | - David Blum
- University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience and Cognition, 59045, Lille, France.
- Alzheimer and Tauopathies, LabEx DISTALZ, LiCEND, 59000, Lille, France.
- NeuroTMULille International Laboratory, Univ. Lille, Lille, France.
- NeuroTMULille International Laboratory, Taipei Medical University, Taipei, 11031, Taiwan.
| | - Thierry Burnouf
- College of Biomedical Engineering, Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, 250 Wu-Xing Street, Taipei, 11031, Taiwan.
- NeuroTMULille International Laboratory, Taipei Medical University, Taipei, 11031, Taiwan.
- International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, 11031, Taiwan.
- International PhD Program in Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- Brain and Consciousness Research Centre, Taipei Medical University Shuang-Ho Hospital, New Taipei City, 23561, Taiwan.
- Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan.
| |
Collapse
|
|
8
|
Reichardt JL, Dirks M, Wirries AK, Pflugrad H, Nösel P, Haag K, Lanfermann H, Wedemeyer H, Potthoff A, Weissenborn K, Ding XQ. Brain metabolic and microstructural alterations associated with hepatitis C virus infection, autoimmune hepatitis and primary biliary cholangitis. Liver Int 2022; 42:842-852. [PMID: 34719118 DOI: 10.1111/liv.15093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 10/24/2021] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Neuropsychiatric symptoms in hepatitis C (HCV) patients resemble those of patients with autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), whilst the mechanisms behind them are unknown. Here we looked for cerebral metabolic and/or microstructural alterations in patients with HCV, AIH or PBC as possible causes behind these symptoms. METHODS Patients with HCV infection (n = 17), AIH (n = 14) or PBC (n = 11) and age-adjusted healthy controls (n = 18) underwent brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and psychometric assessment of memory and attention. Brain relative proton density (PD) and T2 relaxation time (T2) were determined in 17 regions of interest (ROIs), as were the concentrations of N-acetyl-aspartate, choline, creatine, myo-inositol and glutamine + glutamate in frontal- (fWM) and parietal white matter (pWM). One-way analysis of variance and Kruskal-Wallis tests were used for group comparison. Correlations between altered neuropsychological findings and MRI/MRS observations were estimated with the Spearman ρ test. RESULTS HCV, AIH and PBC patients revealed similar alterations in brain PD and metabolites compared to controls: significantly decreased PD in 7/17 ROIs in the HCV group, 16/17 ROIs in the PBC group and 14/17 ROIs in the AIH group, significantly increased N-acetyl-aspartate in fWM in all patients, significantly increased choline in the PBC group in both fWM and pWM, in the AIH group only in pWM and with a trend in the HCV group in pWM. Correlation analysis did not reveal significant associations between MRI/MRS alterations and neuropsychological dysfunction. CONCLUSION The findings suggest similar pathophysiological mechanisms behind neuropsychiatric symptoms associated with HCV infection, AIH and PBC.
Collapse
Affiliation(s)
- Jan-Luca Reichardt
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Meike Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | | | - Henning Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Patrick Nösel
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Kim Haag
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Heinrich Lanfermann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Xiao-Qi Ding
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
9
|
Abstract
PURPOSE OF REVIEW This article describes the neurologic sequelae of various nutritional micronutrient deficiencies, celiac disease, inflammatory bowel disease, and liver disease. Where relevant, appropriate treatments for these conditions are also discussed. The developing field of the microbiome and nervous system interaction is also outlined. RECENT FINDINGS Pathology in the gastrointestinal system can affect the nervous system when it causes micronutrient deficiency, when immune responses created by the gastrointestinal system affect the nervous system, when toxins caused by gastrointestinal organ failure harm the nervous system, and when treatments aimed at a gastrointestinal medical condition cause damage to the nervous system as a side effect. SUMMARY This article addresses familiar concepts and new developments in the treatment and understanding of diseases that affect the gut and nervous system simultaneously.
Collapse
|
|
10
|
Hassaan SH, Darwish AM, Khalifa H, Ramadan HKA, Hassany SM, Ahmed GK, Moustafa EF. Assessment of cognitive functions and psychiatric symptoms in hepatitis C patients receiving pegylated interferon alpha and ribavirin: A prospective cohort study. Int J Psychiatry Med 2019; 54:424-440. [PMID: 31219366 DOI: 10.1177/0091217419858277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Objective This study aimed to prospectively evaluate cognitive functioning in hepatitis C virus patients before, during, and after interferon alpha and to assess the psychiatric side effects of interferon alpha such as depression and anxiety. Methods A total of 100 chronic hepatitis C virus patients eligible for interferon therapy from the hepatitis outpatient clinic of Assiut University Hospital were included. A full medical and psychiatric assessment was done using the Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A). Cognitive assessment was done using The Mini-Mental State Examination (MMSE), Memory Assessment Scales (MAS), and Wechsler Adult Intelligence Scale (WAIS). Medical, cognitive, and psychiatric assessments were conducted at the start of the study and after starting the treatment at two, four, and six months. Results There was a significant increase in the mean scores of HAM-D (t = 7.739, p < 0.001; t = 5.707, p < 0.001; t = 5.115, p < 0.001) and HAM-A (t = 6.237, p < 0.001; t = 4.154, p < 0.001; t = 3.955, p < 0.001) scales at the two, four, and six month follow-ups, respectively, in comparison to the baseline measurements. As regards to the MAS, repeated assessments after two, four, and six months showed no statistically significant difference from the baseline apart from deterioration in the verbal memory performance after six months in comparison to the baseline (t = −2.605, p = 0.011). As regards to MMSE, the verbal intelligence quotient (IQ), performance IQ, and total IQ, there was a significant improvement in the patients’ cognitive performance, in comparison to the baseline, after two months (t = 2.144, p = 0.035), four months (t = 2.868, p = 0.002), and six months (t = 3.505, p = 0.001), respectively. There was also a significant negative correlation between HAM-D mean scores and the MAS verbal mean scores of the patients (r = −.219, p = 0.039). Conclusion There were increases in symptoms of depression and anxiety during interferon alpha and ribavirin treatment, which do not correlate with the patients’ cognitive performance. There was a significant improvement in cognitive performance except in verbal memory with the progress of interferon alpha treatment. Years of education, socioeconomic status, and lower quantitative polymerase chain reaction are predictors for better cognitive performance.
Collapse
Affiliation(s)
- Shehab H Hassaan
- Department of Neurology and Psychiatry, Assiut University, Egypt
| | - Alaa M Darwish
- Department of Neurology and Psychiatry, Assiut University, Egypt
| | - Hossam Khalifa
- Department of Neurology and Psychiatry, Assiut University, Egypt
| | | | - Sahar M Hassany
- Tropical Medicine and Gastroenterlogy, Assiut University, Egypt
| | - Gellan K Ahmed
- Department of Neurology and Psychiatry, Assiut University, Egypt
| | - Ehab F Moustafa
- Tropical Medicine and Gastroenterlogy, Assiut University, Egypt
| |
Collapse
|
|
11
|
Lima S, Faria R, Nery F. Improvement of Central Nervous System Vasculitis in a Patient with Chronic Hepatitis C Virus Infection after Treatment with an Interferon-Free Regimen. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2019; 26:275-278. [PMID: 31328142 PMCID: PMC6624738 DOI: 10.1159/000492066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 06/27/2018] [Indexed: 11/19/2022]
Abstract
BACKGROUND Neurosarcoidosis is a rare manifestation of hepatitis C virus (HCV) infection, mainly in patients exposed to interferon-based therapies. Although we are living in a new era of HCV treatment, there is still little data concerning the treatment of extrahepatic complications of the disease with direct antiviral agents, especially rare ones such as neurosarcoidosis. SUMMARY We present a rare case of central nervous system vasculitic lesions in the context of chronic HCV infection associated with mixed cryoglobulinemia, elevated angiotensin-converting enzyme (ACE) levels, and documentation of viral RNA in the cerebrospinal fluid in a treatment-naïve chronic HCV patient. Successful treatment with an interferon-free regimen improved all clinical manifestations, reduced the levels of serum ACE, and reduced the cryoglobulin levels to undetectable. MESSAGES Neurosarcoidosis and cryoglobulinemia are rare but well-recognized complications of HCV infection, even in treatment-naïve patients. Direct antiviral agents can be useful in the management of this condition.
Collapse
Affiliation(s)
- Sérgio Lima
- Serviço de Medicina Interna, Centro Hospitalar do Porto, Hospital de Santo António, Porto, Portugal
| | - Raquel Faria
- Serviço de Medicina Interna, Centro Hospitalar do Porto, Hospital de Santo António, Porto, Portugal
- Unidade de Imunologia Clínica, Centro Hospitalar do Porto, Hospital de Santo António, Porto, Portugal
| | - Filipe Nery
- Unidade de Transplante Hepato-Pancreática, Centro Hospitalar do Porto, Hospital Santo António, UTHP, Porto, Portugal
- EPIUnit – Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal
- ICBAS – Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal
| |
Collapse
|
|
12
|
Chen VCH, Lu ML, Yang YH, Weng JC, Chang CC. Antidepressant use and hepatocellular carcinoma in patients with hepatitis C who had received interferon therapy: A population-based cohort study. J Affect Disord 2019; 253:147-153. [PMID: 31035215 DOI: 10.1016/j.jad.2019.04.093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/24/2019] [Accepted: 04/21/2019] [Indexed: 01/04/2023]
Abstract
BACKGROUND Using data from the National Health Insurance (NHI) of Taiwan, we conducted a nationwide population-based cohort study to investigate the association between antidepressant (ATD) use and the risk of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) who had received interferon (IFN) therapy. METHODS This study included a total of 274,952 HCV-infected patients without hepatitis B virus infection who were enrolled in the NHI program between January 1, 1997 and December 31, 2013. Among these patients, only 10,713 (age ≥18 years) had received IFN therapy between 2004 and 2008. Among the patients who had received IFN therapy, 2014 had received ATDs, and 8684 had not. A Cox proportional hazards regression model was applied after adjusting for age, sex, income, urbanization, medical comorbidity, and medication use. RESULTS Compared with non-ATD-treated patients, ATD-treated patients were more likely to receive a diagnosis of alcohol-related disease, diabetes mellitus (DM), hypertension, and hyperlipidemia. ATD-treated patients had a significantly lower incidence of HCC than non-ATD-treated patients (P = 0.0019). Female, older (age ≥50 years), and non-DM patients who had received cumulative high doses of ATDs had a significantly lower risk of HCC than non-ATD-treated patients. After adjustment, only high-dose selective serotonin reuptake inhibitor (SSRI) use was inversely associated with HCC risk (adjusted hazard ratio 0.37, 95% confidence interval 0.19-0.71, P = 0.0027). CONCLUSIONS Our study showed that ATD use, especially a relatively high cumulative dose of SSRIs, in HCV-infected patients who had received IFN was associated with reduced HCC risk. Future clinical studies are warranted to explore the underlying mechanisms and to apply them to newer direct-acting antiviral agent treatments.
Collapse
Affiliation(s)
- Vincent Chin-Hung Chen
- School of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Psychiatry, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Mong-Liang Lu
- Department of Psychiatry, Wan Fang Hospital & School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yao-Hsu Yang
- Center of Excellence for Chang Gung Research Datalink, Chang Gung Memorial Hospital, Chiayi, Taiwan; Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan; Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan
| | - Jun-Cheng Weng
- Department of Psychiatry, Chang Gung Memorial Hospital, Chiayi, Taiwan; Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Chen Chang
- Department of Psychiatry, Changhua Christian Hospital, No.135, Nanxiao Street, Changhua 50006, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Center of General Education, Tunghai University, Taichung, Taiwan.
| |
Collapse
|
|
13
|
Dirks M, Haag K, Pflugrad H, Tryc AB, Schuppner R, Wedemeyer H, Potthoff A, Tillmann HL, Sandorski K, Worthmann H, Ding X, Weissenborn K. Neuropsychiatric symptoms in hepatitis C patients resemble those of patients with autoimmune liver disease but are different from those in hepatitis B patients. J Viral Hepat 2019; 26:422-431. [PMID: 30120896 DOI: 10.1111/jvh.12979] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 08/03/2018] [Accepted: 08/07/2018] [Indexed: 12/14/2022]
Abstract
Chronic fatigue, mood alterations and cognitive impairment are frequent accessory symptoms of HCV infection. Fatigue and mood alterations have also been observed in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but not in hepatitis B virus (HBV)-infection, thus indicating an autoimmune response as possible cause of HCV infection-associated encephalopathy. Data, however, are sparse. This study aimed to prove that HCV patients feature similar to those with autoimmune liver disease but contrary to HBV patients regarding neuropsychiatric symptoms. A total of 132 noncirrhotic patients (HCV: 46, HBV: 22, AIH: 27, PBC: 29, AIH/PBC: 8) completed questionnaires addressing the domains mentioned above. Eighty-eight underwent a comprehensive neuropsychological assessment. Patient groups were compared among each other and to 33 healthy controls. Fatigue, anxiety and depression scores were significantly increased, and the SF-36 mental score significantly decreased in all patient groups compared to controls. Fatigue was significantly more pronounced in HCV than in HBV patients. HCV patients scored significantly worse than HBV patients but not AIH and PBC patients in the SF-36. HCV, AIH and PBC but not HBV patients did significantly worse than controls in word learning. Recognition of words was impaired in HCV, AIH and PBC patients and recognition of figures in HCV patients, exclusively (P ≤ 0.002). HCV patients did also worse than controls and HBV patients concerning alertness and working memory (P ≤ 0.001). The neuropsychiatric profiles of HCV patients are similar to those of AIH and PBC patients but differ from those of HBV patients, suggesting an autoimmune response as a possible cause for these differences.
Collapse
Affiliation(s)
- Meike Dirks
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Kim Haag
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Henning Pflugrad
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Anita B Tryc
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Ramona Schuppner
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Andrej Potthoff
- Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hans L Tillmann
- Division of Gastroenterology, Hepatology & Nutrition, East Carolina University, Greenville, North Carolina
| | | | - Hans Worthmann
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Xiaoqi Ding
- Institute for Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | | |
Collapse
|
|
14
|
Aregay A, Dirks M, Schlaphoff V, Owusu Sekyere S, Haag K, Falk CS, Hengst J, Bremer B, Schuppner R, Manns MP, Pflugrad H, Cornberg M, Wedemeyer H, Weissenborn K. Systemic inflammation and immune cell phenotypes are associated with neuro-psychiatric symptoms in patients with chronic inflammatory liver diseases. Liver Int 2018; 38:2317-2328. [PMID: 29710425 DOI: 10.1111/liv.13869] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 04/17/2018] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Chronic inflammatory liver diseases are frequently associated with neuropsychiatric and cognitive dysfunctions. We hypothesized that symptomatic patients may show altered levels of soluble inflammatory mediators (SIMs) as well as changes in immune cell phenotypes. METHODS A comprehensive immune-phenotyping including investigation of 50 SIMs as well as ex-vivo phenotypes of NK-cells, CD3+, CD4+, CD8+ and regulatory T cells in 40 patients with viral and autoimmune chronic liver diseases was performed. The patients' cognitive functions were assessed using an extensive battery of neuropsychological testing. RESULTS AND CONCLUSION Overall, our data indicate that while SIMs are significantly up-regulated, NK- and T-cells are less-activated in patients with neuropsychiatric symptoms accompanying chronic inflammatory liver diseases compared to patients without these symptoms. Moreover, HCV patients showed a unique pattern of immune alterations as compared to patients with HBV, autoimmune hepatitis and primary biliary cirrhosis. These findings hint towards potential mechanisms explaining these symptoms in patients with chronic liver diseases.
Collapse
Affiliation(s)
- Amare Aregay
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Meike Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
| | - Verena Schlaphoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Solomon Owusu Sekyere
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Kim Haag
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Christine Susanne Falk
- Institute of Transplantation Immunology (IFB-Tx), Hannover Medical School, Hannover, Germany.,German Center for Infection Research, Hannover, Germany
| | - Julia Hengst
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ramona Schuppner
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research, Hannover, Germany
| | - Henning Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.,German Center for Infection Research, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany
| | - Karin Weissenborn
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
15
|
Mechanisms of neuropathogenesis in HIV and HCV: similarities, differences, and unknowns. J Neurovirol 2018; 24:670-678. [PMID: 30291565 DOI: 10.1007/s13365-018-0678-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/20/2018] [Accepted: 09/07/2018] [Indexed: 12/17/2022]
Abstract
HIV and hepatitis C virus (HCV) have both been associated with cognitive impairment. Combination antiretroviral therapy (cART) has dramatically changed the nature of cognitive impairment in HIV-infected persons, while the role of direct-acting antivirals (DAA) in neurocognition of HCV-infected individuals remains unclear. Also, whether HIV and HCV interact to promote neurocognitive decline or whether they each contribute an individual effect continues to be an open question. In this work, we review the virally mediated mechanisms of HIV- and HCV-mediated neuropathogenesis, with an emphasis on the role of dual infection, and discuss observed changes with HIV viral suppression and HCV functional cure on neurocognitive impairments.
Collapse
|
|
16
|
Zahr NM. The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity. Front Aging Neurosci 2018; 10:56. [PMID: 29623036 PMCID: PMC5874324 DOI: 10.3389/fnagi.2018.00056] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 02/20/2018] [Indexed: 12/11/2022] Open
Abstract
As successfully treated individuals with Human Immunodeficiency Virus (HIV)-infected age, cognitive and health challenges of normal aging ensue, burdened by HIV, treatment side effects, and high prevalence comorbidities, notably, Alcohol Use Disorders (AUD) and Hepatitis C virus (HCV) infection. In 2013, people over 55 years old accounted for 26% of the estimated number of people living with HIV (~1.2 million). The aging brain is increasingly vulnerable to endogenous and exogenous insult which, coupled with HIV infection and comorbid risk factors, can lead to additive or synergistic effects on cognitive and motor function. This paper reviews the literature on neuropsychological and in vivo Magnetic Resonance Imaging (MRI) evaluation of the aging HIV brain, while also considering the effects of comorbidity for AUD and HCV.
Collapse
Affiliation(s)
- Natalie M Zahr
- Neuroscience Program, SRI International, Menlo Park, CA, United States.,Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
| |
Collapse
|
|
17
|
Kim HM, Lee YH, Han K, Lee BW, Kang ES, Kim J, Cha BS. Impact of diabetes mellitus and chronic liver disease on the incidence of dementia and all-cause mortality among patients with dementia. Medicine (Baltimore) 2017; 96:e8753. [PMID: 29381970 PMCID: PMC5708969 DOI: 10.1097/md.0000000000008753] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
This study investigated the effects of the presence of type 2 diabetes mellitus (T2D) and/or chronic liver disease (CLD) on the incidence and prognosis of dementia during a 10-year period in Korea using a nationwide population-based dataset from the Korea National Health Insurance Service.To assess the impact of T2D and CLD on the incidence of dementia, we included subjects aged ≥60 years without dementia, T2D, and CLD from 2003 to 2005. We created another cohort for evaluating the all-cause mortality in subjects with dementia between 2003 and 2005. The participants were categorized into 4 groups: control (neither CLD nor T2D), CLD-only, T2D-only, and T2D-and-CLD groups, and they were followed up until 2013.The incidence of dementia was higher in the T2D-only group than in the control and CLD-only groups (2.78 vs. 2.04 and 2.00 per 1000 person-years). After adjustment for age, gender, and comorbid conditions, both T2D and CLD increased the risk of any type of dementia; however, the impact of CLD alone was much lower [hazard ratio (HR) 1.07, 95% confidence interval (CI): 1.06-1.08] than that of T2D alone (HR 1.27, 95% CI: 1.27-1.28). The risk of dementia did not significantly change in patients with the co-occurrence of T2D and CLD compared to those with T2D alone. The all-cause mortality rate was the lowest in the control group (2.59 per 1000 person-years) and the highest in the T2D-and-CLD group (3.77 per 1000 person-years). Presence of T2D or CLD alone was associated with higher mortality (HR 1.46 and HR 1.21, respectively) compared with in the absence of both the diseases. Furthermore, the presence of both the diseases further significantly increased the mortality rate compared to the presence of each disease alone (HR 1.67, 95% CI: 1.65-1.69).In conclusion, this study found that the incidence of dementia was much higher in patients with T2D. CLD was associated with a modest increase in risk of dementia; however, there was no additive effect with T2D. In the population with dementia, however, the presence of CLD was associated with high mortality in patients with or without T2D.
Collapse
Affiliation(s)
- Hyun Min Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine
| | - Yong-ho Lee
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Kyungdo Han
- Department of Biostatistics, Catholic University of Korea, Seoul, Korea
| | - Byung-Wan Lee
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Jaetaek Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine
| | - Bong-Soo Cha
- Department of Internal Medicine, Yonsei University College of Medicine
| |
Collapse
|
|
18
|
Dirks M, Pflugrad H, Haag K, Tillmann HL, Wedemeyer H, Arvanitis D, Hecker H, Tountopoulou A, Goldbecker A, Worthmann H, Weissenborn K. Persistent neuropsychiatric impairment in HCV patients despite clearance of the virus?! J Viral Hepat 2017; 24:541-550. [PMID: 28117537 DOI: 10.1111/jvh.12674] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 12/14/2016] [Indexed: 12/30/2022]
Abstract
One of the most disabling symptoms of hepatitis C virus (HCV) infection is chronic fatigue. While this is accepted for HCV polymerase chain reaction (PCR)-positive patients, a relationship between HCV infection and chronic fatigue is questioned after successful virus eradication. As fatigue is a subjective criterion, we aimed to evaluate in addition mood alterations and cognitive function in HCV-exposed patients with only mild liver disease and to assess a) possible interrelationships between these factors and health-related quality of life and b) the impact of viremia and former interferon treatment. One hundred and fifty-nine anti-HCV-positive individuals without advanced liver disease answered health-related quality of life (HRQoL), fatigue and depression questionnaires and underwent a battery of attention and memory tests. Accompanying diseases which could distort the results of the study such as HIV co-infection or drug addiction were exclusion criteria. The patients were subdivided into four groups according to their viremia status and interferon treatment history. Patients' data were evaluated with respect to norms given in the respective test manuals and in addition compared to those of 33 age-matched healthy controls. Eighty-five per cent of the patients had chronic fatigue, 50-60% mild depression or anxiety, 45% memory deficits and 30% attention deficits, irrespective of their HCV viremia status or treatment history. HRQoL correlated negatively with chronic fatigue (P<.001), while cognitive deficits-especially memory function-were independent from fatigue and depression. HCV infection may cause long-standing cerebral dysfunction that significantly impairs HRQoL and may even persist after clearance of the virus.
Collapse
Affiliation(s)
- M Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - K Haag
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H L Tillmann
- Division of Gastroenterology, Hepatology & Nutrition, East Carolina University, Greenville, NC, USA
| | - H Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - D Arvanitis
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Hecker
- Department of Biometrics, Hannover Medical School, Hannover, Germany
| | - A Tountopoulou
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - A Goldbecker
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Worthmann
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - K Weissenborn
- Department of Neurology, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
19
|
Espíndola OM, Vizzoni AG, Lampe E, Andrada-Serpa MJ, Araújo AQC, Leite ACC. Hepatitis C virus and human T-cell lymphotropic virus type 1 co-infection: impact on liver disease, virological markers, and neurological outcomes. Int J Infect Dis 2017; 57:116-122. [PMID: 28185943 DOI: 10.1016/j.ijid.2017.01.037] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 01/26/2017] [Accepted: 01/27/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated with neurological abnormalities, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and peripheral neuropathy (PN). Hepatitis C virus (HCV) infection is the leading cause of chronic liver disease worldwide, and causes PN in approximately 9% of patients. Because the interplay between these potentially neuropathogenic viruses in the same individual is still poorly understood, the clinical and laboratory outcomes of co-infected patients were evaluated and compared with those of controls. METHODS The prevalence rates of neurological and laboratory abnormalities were evaluated in HCV/HTLV-1 co-infected patients (n=50), and in subjects with single HCV (n=46) or HTLV-1 (n=150) infection. RESULTS A higher frequency of isolated PN was present in HCV-infected patients; this was not associated with cryoglobulinemia. No difference was found in the frequency of PN or HAM/TSP when co-infected subjects were compared to singly infected subjects. Hepatic involvement was present in HCV-infected subjects, as shown by increased levels of serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and bilirubin, in addition to thrombocytopenia. On the other hand, HCV/HTLV-1 co-infected individuals presented a better prognosis for hepatic involvement when compared with singly HCV-infected subjects. CONCLUSIONS These data suggest that HCV/HTLV-1 co-infection does not mutualistically alter the outcome with regard to neurological manifestations. Nonetheless, changes in the immunological environment induced by HTLV-1 infection could lead to a reduction in hepatic damage, even without significant HCV clearance.
Collapse
Affiliation(s)
- Otávio M Espíndola
- Laboratory for Clinical Research in Neuroinfections, Evandro Chagas National Institute for Infectious Diseases (INI) - Oswaldo Cruz Foundation (FIOCRUZ), Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil
| | - Alexandre G Vizzoni
- Laboratory for Clinical Research in Neuroinfections, Evandro Chagas National Institute for Infectious Diseases (INI) - Oswaldo Cruz Foundation (FIOCRUZ), Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil
| | - Elisabeth Lampe
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute (IOC) - FIOCRUZ, Rio de Janeiro, Brazil
| | - Maria José Andrada-Serpa
- Laboratory for Clinical Research in Neuroinfections, Evandro Chagas National Institute for Infectious Diseases (INI) - Oswaldo Cruz Foundation (FIOCRUZ), Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil
| | - Abelardo Q C Araújo
- Laboratory for Clinical Research in Neuroinfections, Evandro Chagas National Institute for Infectious Diseases (INI) - Oswaldo Cruz Foundation (FIOCRUZ), Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil
| | - Ana Claudia C Leite
- Laboratory for Clinical Research in Neuroinfections, Evandro Chagas National Institute for Infectious Diseases (INI) - Oswaldo Cruz Foundation (FIOCRUZ), Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil.
| |
Collapse
|
|
20
|
Kasraian L, Negarestani N, Karimi MH, Dehbidi S. A Survey on the Prevalence of Depression in Blood Donors with Hepatitis C in Shiraz. HEPATITIS MONTHLY 2016; 16:e31080. [PMID: 28070197 PMCID: PMC5203680 DOI: 10.5812/hepatmon.31080] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 07/27/2016] [Accepted: 10/05/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Depression is the most common psychiatric disorder associated with hepatitis C. OBJECTIVES This study aimed to survey the prevalence rate of depression in patients with Hepatitis C Virus (HCV) before they were aware of their HCV test result. METHODS This cross-sectional study was conducted on all blood donors with confirmed positive HCV test results who donated blood between March 21, 2012 to March 21, 2013 at Fars blood transfusion center in Iran as case group and age- and sex-matched blood donors with negative screening test results as control group. A semi-structured interview based on DSM IV-TR depressive disorder criteria and Beck depression inventory (BDI) was conducted. BDI contained 21 items, each scored from 0 to 3 and total score of 0 to 63 for the whole scale computed by summing up all the items. A cut-off score of ≥ 19 indicated clinically significant depressive symptoms. The prevalence rate and risk factors of depression were determined. RESULTS The most frequent risk factors for HCV infection were intravenous drug abuse (59.3%), unsafe sexual contact (30.5%), and history of being imprisoned (25.4%). The prevalence rate of depression in the HCV group was 55.9 % (95% CI: 42.99% - 68.87%) that was significantly higher than the corresponding rate of the control group as 17.7 % ( 95% CI: 8.49% - 28.79%) (P < 0.001). The severity of depression was also more in the HCV group (P < 0.001). Besides, the prevalence rate of depression was higher among HCV patients with lower education level, previous history of drug abuse, unsafe sexual contact, and previous history of psychiatric diseases. The prevalence rate of depression was higher in the case group even after adjusting for other variables. CONCLUSIONS Our study underlined the remarkable prevalence of depression among HCV patients. Therefore, designing depression screening tests is suggested to help such patients before starting the treatment.
Collapse
Affiliation(s)
- Leila Kasraian
- Associate Professor, Community Medicine Specialist, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Shiraz, IR Iran
- Corresponding Author: Leila Kasraian, No 164 lane 37 Besat Boulevard, 7174715357 Shiraz, IR Iran. Tel: +98-9177157413, Fax: +98-7116264006, E-mail:
| | - Neda Negarestani
- Assistant Professor, Psychiatrist, Manager of Consultation Center, Iranian Blood Transfusion Research Center, Shiraz, IR Iran
| | - Mohammad Hossein Karimi
- PhD of Immunology, Director, President, Iranian Blood Transfusion Research Center, Shiraz Blood Transfusion Organization, Shiraz, IR Iran
| | - Sahar Dehbidi
- Master of Cellular and Molecular Science, Shiraz, IR Iran
| |
Collapse
|
|
21
|
Weissenborn K, Tillmann HL. HCV encephalopathy - an artefact due to medical care? J Viral Hepat 2016; 23:580-3. [PMID: 27225063 DOI: 10.1111/jvh.12547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 04/26/2016] [Indexed: 12/14/2022]
Abstract
Anti-HCV positive individuals frequently complain about chronic disabling fatigue, mood alterations and deficits in concentration and memory. Several data provide evidence that such alterations are unrelated to hepatitis C virus (HCV) viremia. Thus, merely being exposed to HCV in the past may be sufficient to trigger, but the HCV exposure itself. This commentary reviews the available data upon this topic with special reference to the paper by Lowry and colleagues published in this issue of the Journal of Viral hepatitis. We will carefully discuss scientific reasons, why HCV may be directly involved in the development of neuropsychiatric symptoms independent from ongoing detectable viremia, as suggested by epidemiological data.
Collapse
Affiliation(s)
- K Weissenborn
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - H L Tillmann
- Division of Gastroenterology Hepatology & Nutrition, East Carolina University, Greenville, NC, USA
| |
Collapse
|
|
22
|
Alcohol intake alters immune responses and promotes CNS viral persistence in mice. Behav Brain Res 2016; 312:1-8. [PMID: 27269869 DOI: 10.1016/j.bbr.2016.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 06/01/2016] [Accepted: 06/03/2016] [Indexed: 12/24/2022]
Abstract
Chronic hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic effects, including central nervous system (CNS) damage and neuropsychiatric impairments. Alcohol abuse can exacerbate these adverse effects on brain and behavior, but the molecular mechanisms are not well understood. This study investigated the role of alcohol in regulating viral persistence and CNS immunopathology in mice infected with lymphocytic choriomeningitis virus (LCMV), a model for HCV infections in humans. Female and male BALB/c mice (n=94) were exposed to alcohol (ethanol; EtOH) and water (or water only) using a two-bottle choice paradigm, followed one week later by infection with either LCMV clone 13 (causes chronic infection similar to chronic HCV), LCMV Armstrong (causes acute infection), or vehicle. Mice were monitored for 60days post-infection and continued to receive 24-h access to EtOH and water. Animals infected with LCMV clone 13 drank more EtOH, as compared to those with an acute or no viral infection. Six weeks after infection with LCMV clone 13, mice with EtOH exposure evidenced higher serum viral titers, as compared to mice without EtOH exposure. EtOH intake was also associated with reductions in virus-specific CD8(+) T cell frequencies (particularly CD11a(hi) subsets) and evidence of persistent CNS viremia in chronically infected mice. These findings support the hypothesis that EtOH use and chronic viral infection can result in combined toxic effects accelerating CNS damage and neuropsychiatric dysfunction and suggest that examining the role of EtOH in regulating viral persistence and CNS immunopathology in mice infected with LCMV can lead to a more comprehensive understanding of comorbid alcohol use disorder and chronic viral infection.
Collapse
|
|
23
|
Pflugrad H, Meyer GJ, Dirks M, Raab P, Tryc AB, Goldbecker A, Worthmann H, Wilke F, Boellaard R, Yaqub M, Berding G, Weissenborn K. Cerebral microglia activation in hepatitis C virus infection correlates to cognitive dysfunction. J Viral Hepat 2016; 23:348-57. [PMID: 26768955 DOI: 10.1111/jvh.12496] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 11/02/2015] [Indexed: 01/16/2023]
Abstract
Hepatitis C virus (HCV) infection may induce chronic fatigue and cognitive dysfunction. Virus replication was proven within the brain and HCV-positive cells were identified as microglia and astrocytes. We hypothesized that cerebral dysfunction in HCV-afflicted patients is associated with microglia activation. Microglia activation was assessed in vivo in 22 patients with chronic HCV infection compared to six healthy controls using [(11) C]-PK11195 Positron Emission Tomography (PET) combined with magnetic resonance tomography for anatomical localization. Patients were subdivided with regard to their PCR status, Fatigue Impact Scale score (FIS) and attention test sum score (ATS). A total of 12 patients (54.5%) were HCV PCR positive [of which 7 (58.3%) had an abnormal FIS and 7 (58.3%) an abnormal ATS], 10 patients (45.5%) were HCV PCR negative (5 (50%) each with an abnormal FIS or ATS). Patients without attention deficits showed a significantly higher accumulation of [(11) C]-PK11195 in the putamen (P = 0.05), caudate nucleus (P = 0.03) and thalamus (P = 0.04) compared to controls. Patients with and without fatigue did not differ significantly with regard to their specific tracer binding in positron emission tomography. Preserved cognitive function was associated with significantly increased microglia activation with predominance in the basal ganglia. This indicates a probably neuroprotective effect of microglia activation in HCV-infected patients.
Collapse
Affiliation(s)
- H Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
| | - G-J Meyer
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - M Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - P Raab
- Department of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - A B Tryc
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
| | - A Goldbecker
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
| | - H Worthmann
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - F Wilke
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - R Boellaard
- Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - M Yaqub
- Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - G Berding
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - K Weissenborn
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
24
|
Mathew S, Faheem M, Ibrahim SM, Iqbal W, Rauff B, Fatima K, Qadri I. Hepatitis C virus and neurological damage. World J Hepatol 2016; 8:545-556. [PMID: 27134702 PMCID: PMC4840160 DOI: 10.4254/wjh.v8.i12.545] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 03/19/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.
Collapse
Affiliation(s)
- Shilu Mathew
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Muhammed Faheem
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Sara M Ibrahim
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Waqas Iqbal
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Bisma Rauff
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Kaneez Fatima
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| |
Collapse
|
|
25
|
Liu Y, Chen L, Zou Z, Zhu B, Hu Z, Zeng P, Wu L, Xiong J. Hepatitis C virus infection induces elevation of CXCL10 in human brain microvascular endothelial cells. J Med Virol 2016; 88:1596-603. [PMID: 26895737 DOI: 10.1002/jmv.24504] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2016] [Indexed: 12/27/2022]
Abstract
Hepatitis C virus (HCV) primarily infects liver tissues, while pathogenesis of extrahepatic tissues has been reported. About 50% of patients with HCV infection suffer from neurological disease. The underlying molecular mechanisms remain unclear. In the present study, we aimed to investigate the induction of CXC chemokine ligand 10 (CXCL10) in human brain microvascular endothelial cells (HBMECs) by HCV infection. CXCL10 and its receptor CXCR3 were constitutively expressed in HBMECs. HCV infection induced CXCL10 elevation in HBMECs. The elevation of CXCL10 in HBMECs was eliminated when HCV infection was blocked by neutralizing antibodies. NF-κB is a positive regulator for CXCL10 transcription. HCV infection led to an increased phosphorylation of NF-κB (ser536) in HBMECs, and CXCL10 induced by HCV was slightly decreased when an inhibitor of NF-κB was added. IL1 beta and IFN gama were also upregulated in HCV infected HBMECs, and could be depressed by inhibitor of NF-κB. Thus, HCV infection leads to upregulated expression of CXCL10 in HBMECs, which is probably via the phosphorylation of NF-κB. The findings of this study provide potential mechanisms and novel targets for HCV induced neuroinflammation. J. Med. Virol. 88:1596-1603, 2016. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Yuan Liu
- Clinical Laboratory, General Hospital of Chengdu Military Region of PLA, Chengdu, China
| | - Li Chen
- Clinical Laboratory, General Hospital of Chengdu Military Region of PLA, Chengdu, China
| | - Ziying Zou
- Clinical Laboratory, General Hospital of Chengdu Military Region of PLA, Chengdu, China
| | - Bing Zhu
- Clinical Laboratory, General Hospital of Chengdu Military Region of PLA, Chengdu, China
| | - Zonghai Hu
- Clinical Laboratory, General Hospital of Chengdu Military Region of PLA, Chengdu, China
| | - Ping Zeng
- Clinical Laboratory, General Hospital of Chengdu Military Region of PLA, Chengdu, China
| | - Lijuan Wu
- Clinical Laboratory, General Hospital of Chengdu Military Region of PLA, Chengdu, China
| | - Jie Xiong
- Clinical Laboratory, General Hospital of Chengdu Military Region of PLA, Chengdu, China
| |
Collapse
|
|
26
|
Wozniak MA, Lugo Iparraguirre LM, Dirks M, Deb-Chatterji M, Pflugrad H, Goldbecker A, Tryc AB, Worthmann H, Gess M, Crossey MME, Forton DM, Taylor-Robinson SD, Itzhaki RF, Weissenborn K. Apolipoprotein E-ε4 deficiency and cognitive function in hepatitis C virus-infected patients. J Viral Hepat 2016; 23:39-46. [PMID: 26306786 DOI: 10.1111/jvh.12443] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 07/16/2015] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) causes not only liver damage in certain patients but can also lead to neuropsychiatric symptoms. Previous studies have shown that the type 4 allele of the gene for apolipoprotein E (APOE) is strongly protective against HCV-induced damage in liver. In this study, we have investigated the possibility that APOE genotype is involved in the action of HCV in brain. One hundred HCV-infected patients with mild liver disease underwent a neurological examination and a comprehensive psychometric testing of attention and memory function. In addition, patients completed questionnaires for the assessment of fatigue, health-related quality of life and mood disturbances. Apolipoprotein E gene genotyping was carried out on saliva using buccal swabs. The APOE-ε4 allele frequency was significantly lower in patients with an impairment of working memory, compared to those with a normal working memory test result (P = 0.003). A lower APOE-ε4 allele frequency was also observed in patients with definitely altered attention ability (P = 0.008), but here, the P-value missed the level of significance after application of the Bonferroni correction. Our data suggest that the APOE-ε4 allele is protective against attention deficit and especially against poor working memory in HCV-infected subjects with mild liver disease. Considering the role of apolipoprotein E in the life cycle of the virus, the findings shed interesting new light upon possible pathomechanisms behind the development of neuropsychiatric symptoms in hepatitis C infection.
Collapse
Affiliation(s)
- M A Wozniak
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | | | - M Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - M Deb-Chatterji
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - A Goldbecker
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - A B Tryc
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Worthmann
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - M Gess
- Department of Gastroenterology and Hepatology, St George's Hospital and Medical School, London, UK
| | - M M E Crossey
- Department of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK
| | - D M Forton
- Department of Gastroenterology and Hepatology, St George's Hospital and Medical School, London, UK
| | - S D Taylor-Robinson
- Department of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK
| | - R F Itzhaki
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - K Weissenborn
- Department of Neurology, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
27
|
Monaco S, Mariotto S, Ferrari S, Calabrese M, Zanusso G, Gajofatto A, Sansonno D, Dammacco F. Hepatitis C virus-associated neurocognitive and neuropsychiatric disorders: Advances in 2015. World J Gastroenterol 2015; 21:11974-11983. [PMID: 26576086 PMCID: PMC4641119 DOI: 10.3748/wjg.v21.i42.11974] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 09/11/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Since its identification in 1989, hepatitis C virus (HCV) has emerged as a worldwide health problem with roughly 185 million chronic infections, representing individuals at high risk of developing cirrhosis and liver cancer. In addition to being a frequent cause of morbidity and mortality due to liver disease, HCV has emerged as an important trigger of lymphoproliferative disorders, owing to its lymphotropism, and of a wide spectrum of extra-hepatic manifestations (HCV-EHMs) affecting different organ systems. The most frequently observed HCV-EHMs include mixed cryoglobulinemia and cryoglobulinemic vasculitis, B-cell non-Hodgkin’s lymphoma, nephropathies, thyreopathies, type 2 diabetes mellitus, cardiovascular diseases, and several neurological conditions. In addition, neuropsychiatric disorders and neurocognitive dysfunction are reported in nearly 50% of patients with chronic HCV infection, which are independent of the severity of liver disease or HCV replication rates. Fatigue, sleep disturbance, depression and reduced quality of life are commonly associated with neurocognitive alterations in patients with non-cirrhotic chronic HCV infection, regardless of the stage of liver fibrosis and the infecting genotype. These manifestations, which are the topic of this review, typically occur in the absence of structural brain damage or signal abnormalities on conventional brain magnetic resonance imaging (MRI), although metabolic and microstructural changes can be detected by in vivo proton magnetic resonance spectroscopy, perfusion-weighted and diffusion tensor MRI, and neurophysiological tests of cognitive processing. Several lines of evidence, including comparative and longitudinal neuropsychological assessments in patients achieving spontaneous or treatment-induced viral clearance, support a major pathogenic role for HCV in neuropsychiatric and neurocognitive disorders.
Collapse
|
|
28
|
Gill AJ, Kolson DL. Chronic inflammation and the role for cofactors (hepatitis C, drug abuse, antiretroviral drug toxicity, aging) in HAND persistence. Curr HIV/AIDS Rep 2015; 11:325-35. [PMID: 24929842 DOI: 10.1007/s11904-014-0210-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
HIV-associated neurocognitive disorders (HAND) is a group of syndromes of varying degrees of cognitive impairment affecting up to 50 % of HIV-infected individuals. The neuropathogenesis of HAND is thought to be driven by HIV invasion and productive replication within brain perivascular macrophages and endogenous microglia, and to some degree by restricted infection of astrocytes. The persistence of HAND in individuals experiencing suppression of systemic HIV viral load with antiretroviral therapy (ART) is incompletely explained, and suggested factors include chronic inflammation, persistent HIV replication in brain macrophages, effects of aging on brain vulnerability, and co-morbid conditions including hepatitis C (HCV) co-infection, substance abuse, and CNS toxicity of ART, among other factors. This review discusses several of these conditions: chronic inflammation, co-infection with HCV, drugs of abuse, aging, and antiretroviral drug effects. Effectively managing these co-morbid conditions in individuals with and without HAND is critical for improving neurocognitive outcomes and decreasing HIV-associated morbidity.
Collapse
Affiliation(s)
- Alexander J Gill
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard 280C Clinical Research Building, Philadelphia, PA, 19104, USA,
| | | |
Collapse
|
|
29
|
Sheridan DA, Bridge SH, Crossey MME, Felmlee DJ, Thomas HC, Neely RDG, Taylor-Robinson SD, Bassendine MF. Depressive symptoms in chronic hepatitis C are associated with plasma apolipoprotein E deficiency. Metab Brain Dis 2014; 29:625-34. [PMID: 24615429 DOI: 10.1007/s11011-014-9520-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Accepted: 02/26/2014] [Indexed: 12/20/2022]
Abstract
Neuro-psychiatric and cognitive disorders are frequent in patients with chronic hepatitis C (CHC) virus (HCV) infection which adversely impact quality of life, antiviral treatment adherence and outcome. HCV has neurotrophic properties and affects lipid metabolism, essential for cognitive function. We evaluated the relationship of lipid profiles with depression and anxiety symptoms and the effects of 12-weeks of therapy with fluvastatin and omega-3 ethyl esters (n-3 PUFA) in a randomised pilot study of CHC prior non-responders. Participants (n = 60) had fasting lipid profiles and assessment of depression and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS) questionnaire at each study visit. At screening 26/60 (43 %) had HADS-A score ≥8 and 13/60 (22 %) had HADS-D scores ≥8. Depressed patients had significantly lower apolipoprotein-E concentrations (30 mg/l vs 39 mg/l, P = 0.029) than those without depression and a tendency toward lower total cholesterol (3.8 vs 4.4 mmol/l, P = 0.053). 3 patients discontinued lipid-modifying treatment because of worsening depression. However, there was a small but significant improvement in anxiety symptoms after 12-weeks of high-dose (2-4 g daily) n-3 PUFA. In conclusion, depression in CHC is associated with plasma apoE deficiency. We postulate that apoE deficiency disrupts blood brain barrier integrity to promote HCV infection of the CNS. High-dose n-PUFAs may alleviate anxiety in some CHC patients but the use of lipid lowering therapy must be balanced against risks of worsening depression.
Collapse
Affiliation(s)
- David A Sheridan
- Institute of Cellular Medicine (Hepatology), Newcastle University, William Leech Building, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK,
| | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Hoyo-Becerra C, Liu Z, Yao J, Kaltwasser B, Gerken G, Hermann DM, Schlaak JF. Rapid Regulation of Depression-Associated Genes in a New Mouse Model Mimicking Interferon-α-Related Depression in Hepatitis C Virus Infection. Mol Neurobiol 2014; 52:318-29. [PMID: 25159480 DOI: 10.1007/s12035-014-8861-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Accepted: 08/11/2014] [Indexed: 12/11/2022]
Abstract
Major depression is a serious side effect of interferon-α (IFN-α), which is used in the therapy of hepatitis C virus (HCV) infection. Due to the lack of reproducible animal models, the mechanisms underlying IFN-α-related depression are largely unknown. We herein established a mouse model, in which murine IFN-α (250 IU/day) and polyinosinic/polycytidylic acid (poly(I:C); 1 μg/day), a toll-like receptor-3 (TLR3) agonist that mimics the effect of HCV double-strand RNA, were continuously infused into the lateral ventricle via miniosmotic pumps over up to 14 days. The delivery of IFN-α and poly(I:C), but not of IFN-α or poly(I:C) alone, resulted in a reproducible depression-like state that was characterized by reduced exploration behavior in open-field tests, increased immobility in tail suspension and forced swimming tests, and a moderate loss of body weight. In the hippocampus and prefrontal cortex, the pro-inflammatory genes TNF-α, IL-6, tissue inhibitor of metalloproteinases-1 (Timp-1), CXC motif ligand-1 (Cxcl1), Cxcl10, and CC motif ligand-5 (Ccl5) were synergistically induced by IFN-α and poly(I:C), most pronounced after 14-day exposure. In comparison, the interferon-inducible genes of signal transducer and activator of transcription-1 (Stat1), guanylate binding protein-1 (Gbp1), proteasome subunit-β type-9 (Psmb9), ubiquitin-conjugating enzyme E2L-6 (Ube2l6), receptor transporter protein-4 (Rtp4), and GTP cyclohydrolase-1 (Gch1), which had previously been elevated in the blood of IFN-α-treated patients developing depression, in the brains of suicidal individuals, and in primary neurons exposed to IFN-α and poly(I:C), were induced even earlier, reaching maximum levels mostly after 24 hours. We propose that interferon-inducible genes might be useful markers of imminent depression.
Collapse
Affiliation(s)
- Carolina Hoyo-Becerra
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Challenges in diagnosing hepatic encephalopathy. Neurochem Res 2014; 40:265-73. [PMID: 25142937 DOI: 10.1007/s11064-014-1416-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 08/08/2014] [Accepted: 08/12/2014] [Indexed: 02/07/2023]
Abstract
The term "hepatic encephalopathy" (HE) covers the neuropsychiatric syndrome associated with acute, chronic and acute-on-chronic liver disease (CLD). This paper deals with clinical features and diagnosis of HE in patients with liver cirrhosis and portal hypertension or porto-systemic shunts. The possible impact of concomitant disorders and the cirrhosis underlying liver disease upon brain function is described emphasizing the need of a detailed diagnostic work up of every individual case before diagnosing HE. Currently used methods for diagnosing minimal or covert hepatic encephalopathy are compared with regard to their sensitivity and specificity for diagnosing HE against the background of a multitude of concomitant disorders and diseases that could contribute to brain dysfunction.
Collapse
|
|
32
|
Madsen LW, Fabricius T, Hjerrild S, Hansen TM, Mössner BK, Birkemose I, Skamling M, Christensen PB. Depressive symptoms are frequent among drug users, but not associated with hepatitis C infection. ACTA ACUST UNITED AC 2014; 46:566-72. [PMID: 24934987 DOI: 10.3109/00365548.2014.918274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM To compare the prevalence and severity of depressive symptoms among drug users with and without hepatitis C virus (HCV) infection. METHODS This was a cross-sectional survey study carried out at the 2 major drug treatment centres on the island of Funen, Denmark. Participants were drug users presenting to the 2 treatment centres. Individuals with chronic hepatitis B virus or HIV infection were excluded. Participants completed the Major Depression Inventory (MDI) questionnaire when presenting at the centres. Patients with MDI scores indicating severe depression (total MDI score ≥ 35) were referred for treatment evaluation. Hepatitis C status was classified by the presence of anti-HCV as a marker of HCV exposure and HCV-RNA as a marker of ongoing infection. RESULTS Two hundred and sixty-eight patients were included, of whom 235 (88%) had complete serological testing; 100 (43%, 95% confidence interval (CI) 36-49%) had chronic hepatitis C. The median MDI score was 22 (interquartile range 12-33); 32% (95% CI 26-39%) had a score compatible with depression and 14% (95% CI 10-19%) were rated as severe depression. Depression was not associated with hepatitis C (HCV-infected 29%, non-infected 35%; p = 0.25). Forty-one percent (11/27) of the evaluated participants started antidepressant treatment. CONCLUSIONS Our study demonstrated a high prevalence of depressive symptoms among drug users, but this was not more frequent among HCV-infected patients. The high overall prevalence of depression underlines the relevance of screening for depression in patients who are drug users.
Collapse
Affiliation(s)
- Lone W Madsen
- From the Department of Infectious Diseases, Odense University Hospital , Denmark
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Bajaj JS, Mullen KD, Riggio O. Reply: To PMID 23707462. Clin Gastroenterol Hepatol 2014; 12:707-8. [PMID: 24418090 DOI: 10.1016/j.cgh.2014.01.009] [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: 02/07/2023]
Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia
| | - Kevin D Mullen
- Division of Gastroenterology, Metrohealth Medical Center, Case Western Reserve University, Cleveland, Ohio
| | | |
Collapse
|
|
34
|
Heeren M, Sojref F, Schuppner R, Worthmann H, Pflugrad H, Tryc AB, Pasedag T, Weissenborn K. Active at night, sleepy all day--sleep disturbances in patients with hepatitis C virus infection. J Hepatol 2014; 60:732-40. [PMID: 24308991 DOI: 10.1016/j.jhep.2013.11.030] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 11/23/2013] [Accepted: 11/26/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS More than 50% of patients with chronic hepatitis C with only mild liver disease complain about chronic fatigue, daytime sleepiness and poor sleep quality. The aim of the present study was to characterize and objectify the sleep disturbances in hepatitis C virus-infected patients. METHODS Twenty-five women who had been infected with hepatitis C virus contaminated anti-D immunoglobulin in 1978/79 and 22 age-matched female healthy controls underwent actigraphy over a period of 5 days to measure motor activity and thereby sleep-wake-rhythm and in addition completed questionnaires for depression, health-related quality of life, fatigue and sleep, and a sleep diary. Liver cirrhosis, a history of neurological or psychiatric disease, history of intravenous drug abuse, shift work, or current medication with effect upon the central nervous system were exclusion criteria. RESULTS The patients achieved higher scores for depression, fatigue and sleep disturbances and lower quality of life scores than the healthy controls. Actigraphy showed higher nocturnal activity and worse sleep efficiency in the patients, while the 24-h activity level did not differ between groups. Fatigue and quality of life scores correlated with bad sleep quality and daytime sleepiness. CONCLUSIONS Our data indicate that chronic fatigue is associated with bad sleep quality and increased nocturnal activity in HCV-infected patients suggesting an alteration of sleep architecture behind fatigue in HCV-associated encephalopathy.
Collapse
Affiliation(s)
- Meike Heeren
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Faina Sojref
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Ramona Schuppner
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Hans Worthmann
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Henning Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Anita B Tryc
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Thomas Pasedag
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Karin Weissenborn
- Department of Neurology, Hannover Medical School, Hannover, Germany.
| |
Collapse
|
|
35
|
Toshikuni N, Arisawa T, Tsutsumi M. Hepatitis C-related liver cirrhosis - strategies for the prevention of hepatic decompensation, hepatocarcinogenesis, and mortality. World J Gastroenterol 2014; 20:2876-2887. [PMID: 24659879 PMCID: PMC3961980 DOI: 10.3748/wjg.v20.i11.2876] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 01/13/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a critical stage of chronic liver disease, including that caused by hepatitis C virus (HCV). In the absence of antiviral therapy, 67%-91% of patients with HCV-related LC patients die of liver-related causes, including hepatocellular carcinoma (HCC) and liver failure. Among the therapeutic strategies used to prevent liver-related complications in these patients is standard therapy with pegylated interferon and ribavirin, which induces a sustained virological response (SVR) in 25% of HCV genotype 1-infected patients and in 69% of patients infected with genotypes 2 and 3. SVR in patients with HCV-related LC has been associated with reduced rates of hepatic decompensation, HCC, and mortality. More recently developed direct-acting antiviral agents have shown excellent antiviral efficacy, with preliminary data demonstrating that an interferon-free regimen that includes these direct-acting antiviral agents achieved SVR in more than 50% of patients with HCV genotype 1 LC. Branched-chain amino acid supplementation, improvement of insulin resistance, and the use of β-blockers for portal hypertension may also reduce liver-related complications. Here, we review advances in antiviral and adjunctive therapies for improved outcomes in patients with HCV-associated LC.
Collapse
|
|
36
|
Rempel JD, Krueger C, Minuk GY, Wong SGM. Baseline Comorbidities Enhance the Risk of Treatment-Induced Depression in HCV-Infected Men: A Pilot Study. Am J Mens Health 2014; 8:427-33. [PMID: 24493076 DOI: 10.1177/1557988314521231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is associated with clinical depression,a condition that is aggravated on interferon-based therapy. In HCV infection, men often appear more resilient to depression than women. However, men are subject to depression in diseases that tend to be comorbid in HCV-infected. AIM This study examined whether HCV-infected men with baseline comorbidities were more or less susceptible to depression prior to and on treatment. METHODS Patients with chronic HCV infection preparing to begin treatment participated (n = 37). The presence of baseline comorbidities was determined by pretreatment medication regimes. Depression was measured by the Beck Depression Inventory prior to and following 2, 4, 8, and 12 weeks of interferon therapy. RESULTS At baseline, cohorts with (n = 16) and without (n = 21) comorbidities had equivocal demographics and infection characteristics. Comorbidities did not associate with baseline depression. However, on treatment, men with baseline comorbidities demonstrated an elevated risk for the onset of de novo depression (odds ratio = 19.25; confidence interval = 1.41, 582.14; p = .008). This was not observed for women. Baseline comorbidities did not alter the need for treatment discontinuations or the ability to achieve a sustained viral response. CONCLUSION The results of this study suggest that baseline comorbidities render men more susceptible to interferon treatment-induced depression.
Collapse
Affiliation(s)
- Julia D Rempel
- Section of Hepatology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Carla Krueger
- Section of Hepatology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Gerald Y Minuk
- Section of Hepatology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Stephen G M Wong
- Section of Hepatology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| |
Collapse
|
|
37
|
Apolipoprotein E codetermines tissue tropism of hepatitis C virus and is crucial for viral cell-to-cell transmission by contributing to a postenvelopment step of assembly. J Virol 2013; 88:1433-46. [PMID: 24173232 DOI: 10.1128/jvi.01815-13] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) predominantly infects human hepatocytes, although extrahepatic virus reservoirs are being discussed. Infection of cells is initiated via cell-free and direct cell-to-cell transmission routes. Cell type-specific determinants of HCV entry and RNA replication have been reported. Moreover, several host factors required for synthesis and secretion of lipoproteins from liver cells, in part expressed in tissue-specific fashion, have been implicated in HCV assembly. However, the minimal cell type-specific requirements for HCV assembly have remained elusive. Here we report that production of HCV trans-complemented particles (HCVTCP) from nonliver cells depends on ectopic expression of apolipoprotein E (ApoE). For efficient virus production by full-length HCV genomes, microRNA 122 (miR-122)-mediated enhancement of RNA replication is additionally required. Typical properties of cell culture-grown HCV (HCVcc) particles from ApoE-expressing nonliver cells are comparable to those of virions derived from human hepatoma cells, although specific infectivity of virions is modestly reduced. Thus, apolipoprotein B (ApoB), microsomal triglyceride transfer protein (MTTP), and apolipoprotein C1 (ApoC1), previously implicated in HCV assembly, are dispensable for production of infectious HCV. In the absence of ApoE, release of core protein from infected cells is reduced, and production of extracellular as well as intracellular infectivity is ablated. Since envelopment of capsids was not impaired, we conclude that ApoE acts after capsid envelopment but prior to secretion of infectious HCV. Remarkably, the lack of ApoE also abrogated direct HCV cell-to-cell transmission. These findings highlight ApoE as a host factor codetermining HCV tissue tropism due to its involvement in a late assembly step and viral cell-to-cell transmission.
Collapse
|
|
38
|
Measuring the response of extrahepatic symptoms and quality of life to antiviral treatment in patients with hepatitis C. HEPATITIS RESEARCH AND TREATMENT 2013; 2013:910519. [PMID: 24223303 PMCID: PMC3816051 DOI: 10.1155/2013/910519] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 09/17/2013] [Accepted: 09/18/2013] [Indexed: 12/24/2022]
Abstract
Background. HCV infection is associated with musculoskeletal manifestations such as chronic widespread pain, sicca syndrome, polyarthritis, and a reduced HRQOL. Little data is available on the effect of treatment on these manifestations. This study measured changes in extrahepatic symptoms and HRQOL before and after antiviral treatment in a large UK patient cohort. Methods. 118 patients completed HQLQ and rheumatological questionnaires before and after treatment with pegylated interferon-α and ribavirin, with specific regard to chronic widespread pain, sicca syndrome, and sustained virological response. Results. There was significant improvement in HQLQ domains of physical functioning, physical disability, social functioning, limitations and health distress due to hepatitis, and general health. There was significant deterioration in domains of positive well-being, health distress, and mental health. There was a significant decline prevalence of CWP (26.3% versus 15.3%, P = 0.015). Sicca syndrome prevalence fell insignificantly (12.7% versus 11%). SVR was associated positively with all HRQOL changes and significantly with CWP remission. Conclusions. HCV antivirals significantly improve poor HRQOL scores and CWP. Before treatment, both were common, coassociated, and unaccounted for through mixed cryoglobulinemia alone. Although a role of the hepatitis C virus in CWP cannot be deduced by these results, symptomatic improvement via antiviral treatment exists for this subset of patients.
Collapse
|
|
39
|
Branch AD, Drye LT, Van Natta ML, Sezgin E, Fishman SL, Dieterich DT, Meinert CL, Jabs DA. Evaluation of hepatitis C virus as a risk factor for HIV-associated neuroretinal disorder. Clin Infect Dis 2013; 57:1618-25. [PMID: 24081683 DOI: 10.1093/cid/cit550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Both hepatitis C virus (HCV) and human immunodeficiency virus (HIV) penetrate the central nervous system. HIV-associated neuroretinal disorder (HIV-NRD), a visual impairment of reduced contrast sensitivity and reading ability, is associated with cytokine dysregulation and genetic polymorphisms in the anti-inflammatory interleukin 10 (IL-10) signaling pathway. We investigated associations between HCV and HIV-NRD and between HCV and single-nucleotide polymorphisms (SNPs) in the IL-10 receptor 1 (IL10R1) gene. METHODS Logistic and Cox regression analysis were used to analyze risk factors for HIV-NRD in 1576 HIV-positive patients who did not have an ocular opportunistic infection at enrollment. Median follow-up was 4.9 years (interquartile range, 2.4-8.8 years). Four IL10R1 SNPs were examined in a subset of 902 patients. RESULTS The group included 290 patients with chronic HCV infection, 74 with prior infection, and 1212 with no HCV markers. There were 244 prevalent cases of HIV-NRD and 263 incident cases (rate = 3.9/100 person-years). In models adjusted for demographics, HIV treatment and status, liver function, and immune status, both the prevalence and incidence of HIV-NRD were significantly higher in patients with chronic HCV infection (odds ratio = 1.54; 95% confidence interval [CI], 1.03-2.31 and hazard ratio = 1.62; 95% CI, 1.13-2.34, respectively), compared to patients with no HCV markers. Chronic HCV was associated with rs2228055 and 2 additional IL-10R1 SNPs expected to reduce IL-10 signaling. HIV-NRD was not significantly associated with these SNPs. CONCLUSIONS HCV is a possible risk factor for HIV-NRD. Genetic analysis suggests that alterations in the IL-10 signaling pathway may increase susceptibility to HIV-NRD and HCV infection. Inflammation may link HCV and HIV-NRD.
Collapse
Affiliation(s)
- Andrea D Branch
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Kraus MR, Schäfer A, Teuber G, Porst H, Sprinzl K, Wollschläger S, Keicher C, Scheurlen M. Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Hepatology 2013; 58:497-504. [PMID: 23300053 DOI: 10.1002/hep.26229] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 11/01/2012] [Indexed: 12/30/2022]
Abstract
UNLABELLED Earlier studies have suggested neurocognitive impairment in patients with chronic hepatitis C virus (HCV) infection even before liver cirrhosis has developed. Since these deficits might be reversible after successful antiviral therapy, we analyzed the long-term course of neurocognitive parameters in HCV patients with and without successful virus elimination by an interferon-based antiviral treatment. In a multicenter study including 168 HCV patients receiving antiviral therapy (peginterferon alpha-2b and ribavirin) we performed a long-term follow-up of neurocognitive performance before and after treatment. Neurocognitive function was psychometrically assessed using the computer-aided TAP (Test Battery of Attentional Performance). When tested at least 12 months after termination of antiviral treatment, patients with sustained virologic response (SVR) had improved significantly as compared to their pretreatment performance in three of five TAP subtasks (vigilance, P < 0.001; shared attention: optical task, P < 0.001; working memory, P < 0.001). Patients who failed to eradicate the virus, however, showed no significant long-term changes in neurocognitive performance in all five subtasks assessed (0.194 < P < 0.804). In the posttreatment evaluation, neurocognitive function was significantly better in responders to the antiviral therapy as compared to nonresponders. CONCLUSION Successful eradication of HCV leads to a significant improvement of relevant aspects of attentional and neurocognitive performance, indicating that the neurocognitive impairment caused by chronic HCV infection is potentially reversible. This therefore suggests an added therapeutic benefit of antiviral treatment in HCV infection. Improvement of neurocognitive function may be an additional treatment indication in patients with HCV. (HEPATOLOGY 2013;58:497-504).
Collapse
Affiliation(s)
- Michael R Kraus
- Medizinische Klinik und Poliklinik II, Department of Gastroenterology, University of Würzburg, Würzburg, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Bajaj JS, Forton DM. Cognitive improvement after HCV eradication: Extending the benefits. Hepatology 2013; 58:480-2. [PMID: 23696270 DOI: 10.1002/hep.26481] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 04/08/2013] [Accepted: 04/13/2013] [Indexed: 01/18/2023]
Affiliation(s)
- Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology and Nutrition; Virginia Commonwealth University, and McGuire VA Medical Center; Richmond VA
| | - Daniel M. Forton
- Department of Gastroenterology and Hepatology; St George's University of London; London UK
| |
Collapse
|
|
42
|
A Metabolomics Profiling Study in Hand-Foot-and-Mouth Disease and Modulated Pathways of Clinical Intervention Using Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:647452. [PMID: 23533509 PMCID: PMC3590494 DOI: 10.1155/2013/647452] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 12/23/2012] [Accepted: 12/28/2012] [Indexed: 12/16/2022]
Abstract
Hand-foot-and-mouth disease (HFMD), with poorly understood pathogenesis, has become a major public health threat across Asia Pacific. In order to characterize the metabolic changes of HFMD and to unravel the regulatory role of clinical intervention, we have performed a metabolomics approach in a clinical trial. In this study, metabolites profiling was performed by liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) platform from the HFMD clinical patient samples. The outcome of this study suggested that 31 endogenous metabolites were mainly involved and showed marked perturbation in HFMD patients. In addition, combination therapy intervention showed normalized tendency in HFMD patients in differential pathway. Taken together, these results indicate that metabolomics approach can be used as a complementary tool for the detection and the study of the etiology of HFMD.
Collapse
|
|
43
|
Abstract
Due to the obligatory intracellular lifestyle of viruses, cell culture systems for efficient viral propagation are crucial to obtain a detailed understanding of the virus-host cell interaction. For hepatitis C virus (HCV) the development of permissive and authentic culture models continues to be a challenging task. The first efforts to culture HCV had limited success and range back to before the virus was molecularly cloned in 1989. Since then several major breakthroughs have gradually overcome limitations in culturing the virus and sequentially permitted analysis of viral RNA replication, cell entry, and ultimately the complete replication cycle in cultured cells in 2005. Until today, basic and applied HCV research greatly benefit from these tremendous efforts which spurred multiple complementary cell-based model systems for distinct steps of the HCV replication cycle. When used in combination they now permit deep insights into the fascinating biology of HCV and its interplay with the host cell. In fact, drug development has been much facilitated and our understanding of the molecular determinants of HCV replication has grown in parallel to these advances. Building on this groundwork and further refining our cellular models to better mimic the architecture, polarization and differentiation of natural hepatocytes should reveal novel unique aspects of HCV replication. Ultimately, models to culture primary HCV isolates across all genotypes may teach us important new lessons about viral functional adaptations that have evolved in exchange with its human host and that may explain the variable natural course of hepatitis C.
Collapse
Affiliation(s)
- Eike Steinmann
- Helmholtz Centre for Infection Research, Hannover, Germany
| | | |
Collapse
|
|
44
|
Abstract
OBJECTIVE Decreased appetite is one of the main factors that influences quality of life of patients with chronic liver diseases. The reason for appetite disorders remains unclear but taste perturbations are one of the postulated causes. The potential role of taste alterations and, connected to these, appetite disorders in chronic hepatitis C (CHC) patients are poorly investigated. The aim of this study was to evaluate potential taste alterations (dysgeusia) including all five tastes (sweet, salty, bitter, sour and umami) in CHC patients. METHODS Forty CHC patients (16 men and 24 women) infected with genotype 1 hepatitis C virus participated in this study. All the patients had a compensated liver disease and were being treated with any agents. One hundred and ten healthy volunteers were matched to the patients by age and sex. The study included gustatory tests (taste recognition threshold, taste intensity with hedonic perception) and analysis of the pleasure derived from eating. RESULTS In CHC patients, the recognition threshold of umami taste was increased (P<0.01) and the intensity of sweet taste perception was higher (P<0.05). The hedonic response did not differ between the groups. A significant increase in declared pleasure derived from eating (P<0.001 to P<0.05) was also observed. Some differences in case of the patients with more advanced disease were also found. CONCLUSION Alterations in taste, especially umami and sweet taste disorders, may alter real food perception and lead to a reduction in food intake in some CHC patients.
Collapse
|
|
45
|
White matter abnormalities correlate with neurocognitive performance in patients with HBV-related cirrhosis. J Neurol Sci 2012; 321:65-72. [PMID: 22877508 DOI: 10.1016/j.jns.2012.07.056] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2012] [Revised: 07/22/2012] [Accepted: 07/24/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND White matter (WM) abnormalities are common in cirrhotic patients and possibly contribute to hepatic encephalopathy (HE), a frequent neuropsychiatric complication of cirrhosis. However, little is known about these WM abnormalities and their relationship to neurocognitive deficits in patients with HBV-related cirrhosis. METHODS Three-dimensional T1-weighted magnetic resonance imaging and diffusion tensor imaging (DTI) scans were obtained from 67 patients with HBV-related cirrhosis and 40 controls. Voxel-based morphometry and voxel-based DTI were performed to detect macroscopic atrophy and damage to the microstructural integrity of the WM, respectively. Correlation analyses were performed to investigate the relationships between WM abnormalities and neurocognitive performances. RESULTS Patients with cirrhosis exhibited significantly decreased WM volume and fractional anisotropy (FA) values, especially in the corpus callosum, thalamus, extra-nuclear area, sensorimotor area, fusiform gyrus, lingual gyrus, and frontal lobes. These abnormalities were more severe with increasing Child-Pugh stage, minimal HE, and previous overt HE. Changes in the corpus callosum, frontal lobe, sensorimotor area, internal capsule, and temporal-occipital lobes were correlated with poor neurocognitive performance. Also, the significantly decreased global WM volume and mean FA value were correlated with poor neurocognitive performances. CONCLUSIONS Diffuse WM abnormalities are common in patients with HBV-related cirrhosis. Advanced liver disease and episodes of HE are two factors associated with WM abnormalities. The correlation between poor neurocognitive performance and WM abnormalities suggests that WM abnormalities may be one of mechanisms underlying neurocognitive deficits in patients with HBV-related cirrhosis.
Collapse
|
|
46
|
Abstract
Chronic infection with hepatitis C virus (HCV) is associated with a wide spectrum of extrahepatic manifestations, affecting different organ systems. Neurological complications occur in a large number of patients and range from peripheral neuropathy to cognitive impairment. Pathogenetic mechanisms responsible for nervous system dysfunction are mainly related to the upregulation of the host immune response with production of autoantibodies, immune complexes, and cryoglobulins. Alternative mechanisms include possible extrahepatic replication of HCV in neural tissues and the effects of circulating inflammatory cytokines and chemokines.
Collapse
|
|
47
|
Amodio P, Salari L, Montagnese S, Schiff S, Neri D, Bianco T, Minazzato L. Hepatitis C virus infection and health-related quality of life. World J Gastroenterol 2012; 18:2295-9. [PMID: 22654420 PMCID: PMC3353363 DOI: 10.3748/wjg.v18.i19.2295] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Revised: 01/14/2012] [Accepted: 02/08/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) hepatitis and other diseases related to HCV, such as cryoglobulinemia, lymphoma and renal failure, impair health-related quality of life (HRQoL). In addition, HCV per se might directly influence HRQoL via colonization of microglia in the brain or, indirectly, via the effect of systemic inflammatory cytokines which, in turn, can trigger brain interleukin production. The treatment of HCV-related disorders with interferon (IFN) has an effect on HRQoL. Initially, IFN causes a transient deterioration of HRQoL, due to the induction of depression and other side effects of treatment. Subsequently, the subjects who obtain a sustained virologic response experience an improvement in HRQoL. Only rarely does interferon treatment causes permanent detrimental effects on HRQoL, due to residual psychiatric or neurologic side effects. Liver transplantation is the only treatment for end-stage HCV-related liver disease. HRQoL generally improves massively a few months after transplantation, except in the case of serious complications of the transplant procedure. Furthermore, high levels of anxiety and neuroticism pre-transplant are associated with lower HRQoL one year after transplant. Additionally, six months after transplant, patients with HCV who experience virologic recurrence show significantly greater depression, anxiety, phobic anxiety, and paranoid ideation than anti-HCV-negative patients. In conclusion, optimal care for the overall well-being of patients with HCV infection requires adequate knowledge of their neurological and psychological status.
Collapse
|
|
48
|
Abstract
PURPOSE OF REVIEW The prevalence of psychiatric co-morbidity in injecting drug users (IDUs) in the Western countries is high and is associated with lower quality of life and reduces the effectiveness of treatment programs. The aim of this study is to provide a review about psychiatric comorbidity in IDUs in Asia and Africa, where HIV prevalence is high and still increasing. RECENT FINDINGS Studies focusing on psychiatric comorbidity in Asia and Africa are scarce. The prevalence of psychiatric comorbidity is comparable with the prevalence in western countries. Psychiatric disorders can occur before or during drug abuse and are also associated with substance abuse and physical comorbidity and its treatments. Childhood trauma followed by post-traumatic disorders is a significant risk factor for substance abuse. Psychiatric co-occurring disorders influence the adherence to the physical and drug use treatment. Evidence-based treatment for psychiatric comorbidity in IDUs is still limited. SUMMARY A better understanding of the prevalence of psychiatric disorders in IDUs and its impact on the overall treatments is growing. However, more studies focusing on the treatment for psychiatric comorbidity in IDUs in Asia and Africa are needed.
Collapse
|
|
49
|
Abstract
Hepatitis C virus (HCV) is an enveloped, positive-strand RNA virus of the family Flaviviridae that primarily infects hepatocytes, causing acute and chronic liver disease. HCV is also associated with a variety of extrahepatic symptoms including central nervous system (CNS) abnormalities, cognitive dysfunction, fatigue and depression. These symptoms do not correlate with the severity of liver disease and are independent of hepatic encephalopathy. HCV RNA has been associated with CNS tissue, and reports of viral sequence diversity between brain and liver tissue suggest independent viral evolution in the CNS and liver. This review will explore the data supporting HCV infection of the CNS and how this fits into our current understanding of HCV pathogenesis.
Collapse
Affiliation(s)
- N F Fletcher
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK.
| | | |
Collapse
|
|
50
|
Meredith LW, Wilson GK, Fletcher NF, McKeating JA. Hepatitis C virus entry: beyond receptors. Rev Med Virol 2012; 22:182-93. [PMID: 22392805 DOI: 10.1002/rmv.723] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 09/30/2011] [Accepted: 10/09/2011] [Indexed: 12/11/2022]
Abstract
HCV is a blood-borne pathogen that affects approximately 3% of the global population and leads to progressive liver disease. Recent advances have identified an essential role for host cell molecules: tetraspanin CD81, scavenger receptor B1 and the tight junction proteins claudin-1 and occludin in HCV entry, suggesting a complex multi-step process. The conserved nature of this receptor-dependent step in the viral life cycle offers an attractive target for therapeutic intervention. Evidence is emerging that additional factors other than classical receptors, such as inflammatory mediators regulate the ability of hepatocytes to support HCV entry, and as such may provide potential avenues for drug design and development. In this review, we summarise the recent literature on HCV entry mechanisms with a view to realising the future potential of therapeutically targeting this process.
Collapse
Affiliation(s)
- Luke W Meredith
- Institute for Biomedical Research, University of Birmingham, Birmingham, UK
| | | | | | | |
Collapse
|