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Li W, Zhang J, Gao Y, Kong X, Sun X. Nervous system in hepatocellular carcinoma: Correlation, mechanisms, therapeutic implications, and future perspectives. Biochim Biophys Acta Rev Cancer 2025; 1880:189345. [PMID: 40355012 DOI: 10.1016/j.bbcan.2025.189345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 04/30/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous and complex cancer influenced by both the tumor microenvironment and multi-level regulation of the nervous system. Increasing evidence highlights critical roles of the central nervous system (CNS) and peripheral nervous system (PNS) in modulating HCC progression. Psychological stress and emotional disturbances, representing CNS dysregulation, directly accelerate tumor growth, metastasis, and impair anti-tumor immunity in HCC. PNS involvement, particularly autonomic innervation, extensively reshapes the hepatic tumor microenvironment. Specifically, sympathetic activation promotes immune suppression, tumor cell proliferation, epithelial-mesenchymal transition (EMT), and cancer stemness via β-adrenergic signaling and hypoxia-inducible factor 1-alpha (HIF-1α) stabilization, whereas parasympathetic signals generally exert anti-inflammatory and tumor-suppressive effects mediated by acetylcholine. Neurotransmitters including epinephrine, norepinephrine, dopamine, serotonin, and acetylcholine precisely regulate critical pathways such as AKT/mTOR, ERK, and NF-κB, thereby driving malignant cell behaviors, immune evasion, and chemoresistance. Neuro-targeted pharmacological interventions (e.g., SSRIs, β-blockers, dopamine antagonists) and behavioral therapies have shown efficacy in preclinical studies, underscoring their therapeutic potential. Additionally, neural-associated biomarkers like NEDD9, CNTN1, and nerve growth factor (NGF) exhibit prognostic significance, supporting their future clinical application. By systematically integrating neuroscience with oncology, this review identifies innovative neural-based therapeutic strategies, highlights key mechanistic insights, and outlines promising directions for future research and personalized clinical management of HCC.
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Affiliation(s)
- Wenxuan Li
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China
| | - Jinghao Zhang
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China
| | - Yueqiu Gao
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
| | - Xuehua Sun
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
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2
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Zimbrean PC, Jakab SS. Depression and anxiety management in cirrhosis. Hepatol Commun 2025; 9:e0600. [PMID: 39670879 PMCID: PMC11637748 DOI: 10.1097/hc9.0000000000000600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 11/04/2024] [Indexed: 12/14/2024] Open
Abstract
Depressive and anxiety symptoms are more prevalent in patients with cirrhosis compared to the general population. Between 2009 and 2019, the prevalence of depression in cirrhosis increased by 80%, while the prevalence of generalized anxiety disorder increased by over 400%. When present, anxiety and depression are linked to lower health-related quality of life, more severe symptoms (eg, fatigue), and poorer response to medical treatment. Screening instruments for depression and anxiety have shown acceptable validity in patients with cirrhosis. However, the diagnosis of depression and anxiety disorder remains challenging in this population and should follow the established criteria for general populations. Treatment interventions are numerous and include patient education and support around liver disease, pharmacological agents, and psychotherapy. Antidepressants are the treatment of choice for patients with depressive or anxiety disorder and cirrhosis. However, consideration must be given to dose adjustment and choice of agent due to changes in their metabolism in patients with liver disease. Psychotherapy may be used as a stand-alone therapy or concomitantly with pharmacotherapy. The high prevalence and complexity of depressive and anxiety symptoms in patients with cirrhosis support the integrated care approach in which patients are cared for by multidisciplinary teams.
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Affiliation(s)
- Paula C. Zimbrean
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
| | - Simona S. Jakab
- Department of Medicine (Digestive Disease), Yale School of Medicine, New Haven, Connecticut, USA
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3
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Cooper KM, Colletta A, Osorio B, Herringshaw E, Talat A, Devuni D. History of Depression is Associated With Higher Prevalence of Hepatic Encephalopathy in Patients With Advanced Liver Disease. Am J Med 2024; 137:872-879.e2. [PMID: 38729591 DOI: 10.1016/j.amjmed.2024.04.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 04/19/2024] [Accepted: 04/24/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Depression and hepatic encephalopathy are common in patients with advanced liver disease. Although these are distinct entities, they share several clinical features. In this analysis, we evaluated whether having a history of depression was associated with developing hepatic encephalopathy in patients with advanced liver disease. METHODS We performed a retrospective cohort study of patients with cirrhosis referred for liver transplant. Patients were categorized into 1 of 2 groups: "history of depression" or "no history of depression." Multivariable logistic regression was used to evaluate history of depression as a potential independent predictor of hepatic encephalopathy. RESULTS A total of 447 patients were included, of which 158 (35%) had a history of depression and 233 (52%) had experienced hepatic encephalopathy. Hepatic encephalopathy was more common in patients with a history of depression (63% vs 46%, P < .01). On multivariate analyses, depression history was independently associated with hepatic encephalopathy (aOR 2.3, 95% CI 1.4-3.6), along with alcohol associated cirrhosis (aOR 2.0, 95% CI 1.3-3.2), history of ascites (aOR 3.5, 95% CI 2.1-5.9) and presence of a trans-jugular intra-hepatic shunt (aOR 9.2, 95% CI 2.6-32.6). The relationship between history of depression and hepatic encephalopathy remained significant in a subgroup of patients with alcohol associated liver disease (P = .04). Among those with a history of depression, SNRI prescription was more common in the hepatic encephalopathy group (14% vs 3%), and SNRI prescription was as an independent predictor of hepatic encephalopathy in the multivariable model (OR 4.8, 95% CI 1.0-24.6) CONCLUSIONS: Patients with a history of depression were significantly more likely to experience hepatic encephalopathy. Patients with cirrhosis who have a history of depression should be closely monitored for the development of hepatic encephalopathy. Further research is needed to understand the nuances of this relationship and whether the use of certain psychiatric medications may modify the relationship between depression and hepatic encephalopathy.
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Affiliation(s)
- Katherine M Cooper
- Department of Medicine, University of Mass Chan Medical School, Worcester
| | | | - Brian Osorio
- Department of Medicine, University of Mass Chan Medical School, Worcester
| | - Emilee Herringshaw
- Department of Medicine, University of Mass Chan Medical School, Worcester
| | - Arslan Talat
- Department of Medicine, University of Mass Chan Medical School, Worcester; Division of Gastroenterology and Hepatology, Department of Medicine, UMass Chan Medical School, Worcester
| | - Deepika Devuni
- Department of Medicine, University of Mass Chan Medical School, Worcester; Division of Gastroenterology and Hepatology, Department of Medicine, UMass Chan Medical School, Worcester.
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4
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Kwete XJ, Bhadelia A, Arreola-Ornelas H, Mendez O, Rosa WE, Connor S, Downing J, Jamison D, Watkins D, Calderon R, Cleary J, Friedman JR, De Lima L, Ntizimira C, Pastrana T, Pérez-Cruz PE, Spence D, Rajagopal MR, Vargas Enciso V, Krakauer EL, Radbruch L, Knaul FM. Global Assessment of Palliative Care Need: Serious Health-Related Suffering Measurement Methodology. J Pain Symptom Manage 2024; 68:e116-e137. [PMID: 38636816 PMCID: PMC11253038 DOI: 10.1016/j.jpainsymman.2024.03.027] [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: 01/31/2024] [Revised: 03/05/2024] [Accepted: 03/27/2024] [Indexed: 04/20/2024]
Abstract
CONTEXT Inequities and gaps in palliative care access are a serious impediment to health systems especially in low- and middle-income countries and the accurate measurement of need across health conditions is a critical step to understanding and addressing the issue. Serious Health-related Suffering (SHS) is a novel methodology to measure the palliative care need and was originally developed by The Lancet Commission on Global Access to Palliative Care and Pain Relief. In 2015, the first iteration - SHS 1.0 - was estimated at over 61 million people worldwide experiencing at least 6 billion days of SHS annually as a result of life-limiting and life-threatening conditions. OBJECTIVES In this paper, an updated methodology - SHS 2.0 - is presented building on the work of the Lancet Commission and detailing calculations, data requirements, limitations, and assumptions. METHODS AND RESULTS The updates to the original methodology focus on measuring the number of people who die with (decedents) or live with (non-decedents) SHS in a given year to assess the number of people in need of palliative care across health conditions and populations. Detail on the methodology for measuring the number of days of SHS that was pioneered by the Lancet Commission, is also shared, as this second measure is essential for determining the health system responses that are necessary to address palliative care need and must be a priority for future methodological work on SHS. CONCLUSIONS The methodology encompasses opportunities for applying SHS to future policy making assessment of future research priorities particularly in light of the dearth of data from low- and middle-income countries, and sharing of directions for future work to develop SHS 3.0.
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Affiliation(s)
- Xiaoxiao J Kwete
- University of Miami Institute for Advanced Study of the Americas, University of Miami (X.J.K., A.B., H.A.-O., W.E.R., R.C., V.V.E., F.M.K.), Miami, Florida, USA; Yangzhou Philosophy and Social Science Research and Communication Center (X.J.K.), Yangzhou, China.
| | - Afsan Bhadelia
- University of Miami Institute for Advanced Study of the Americas, University of Miami (X.J.K., A.B., H.A.-O., W.E.R., R.C., V.V.E., F.M.K.), Miami, Florida, USA; Department of Public Health, College of Health and Human Sciences (A.B.), Purdue University, West Lafayette, Indiana, USA
| | - Héctor Arreola-Ornelas
- University of Miami Institute for Advanced Study of the Americas, University of Miami (X.J.K., A.B., H.A.-O., W.E.R., R.C., V.V.E., F.M.K.), Miami, Florida, USA; Institute for Obesity Research, Tecnologico de Monterrey (H.A.-O.), Monterrey, Mexico; School of Government and Public Transformation, Tecnologico de Monterrey, Mexico City, Mexico; Tómatelo a Pecho, A.C. (H.A-O., O.M., F.M.K.), Mexico City, Mexico; Fundación Mexicana para la Salud (FUNSALUD) (H.A.-O.), Mexico City, México
| | - Oscar Mendez
- Tómatelo a Pecho, A.C. (H.A-O., O.M., F.M.K.), Mexico City, Mexico
| | - William E Rosa
- University of Miami Institute for Advanced Study of the Americas, University of Miami (X.J.K., A.B., H.A.-O., W.E.R., R.C., V.V.E., F.M.K.), Miami, Florida, USA; Department of Psychiatry and Behavioral Sciences (W.E.R.), Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Stephen Connor
- Worldwide Hospice Palliative Care Alliance (S.C.), London, UK
| | - Julia Downing
- International Children's Palliative Care Network (J.D.), Bristol, UK
| | - Dean Jamison
- University of California (D.J.), San Francisco, California, USA
| | - David Watkins
- Department of Global Health, University of Washington (D.W.), Seattle, Washington, USA
| | - Renzo Calderon
- University of Miami Institute for Advanced Study of the Americas, University of Miami (X.J.K., A.B., H.A.-O., W.E.R., R.C., V.V.E., F.M.K.), Miami, Florida, USA
| | - Jim Cleary
- Indiana University School of Medicine (J.C.), Indianapolis, Indiana, USA
| | - Joseph R Friedman
- Center for Social Medicine and Humanities, University of California, Los Angeles, California, USA
| | - Liliana De Lima
- International Association of Hospice and Palliative Care (L.D.L.), Houston, Texas, USA
| | | | - Tania Pastrana
- International Association of Hospice and Palliative Care (L.D.L.), Houston, Texas, USA; Department of Palliative Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Pedro E Pérez-Cruz
- Sección Medicina Paliativa, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro para la Prevención y el Control del Cáncer (CECAN), Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | | | - Valentina Vargas Enciso
- University of Miami Institute for Advanced Study of the Americas, University of Miami (X.J.K., A.B., H.A.-O., W.E.R., R.C., V.V.E., F.M.K.), Miami, Florida, USA
| | - Eric L Krakauer
- Department of Global Health & Social Medicine, Harvard Medical School (E.L.K.), Boston, Massachusetts, USA
| | - Lukas Radbruch
- International Association of Hospice and Palliative Care (L.D.L.), Houston, Texas, USA; Department of Palliative Medicine, University Hospital Bonn, Germany
| | - Felicia Marie Knaul
- University of Miami Institute for Advanced Study of the Americas, University of Miami (X.J.K., A.B., H.A.-O., W.E.R., R.C., V.V.E., F.M.K.), Miami, Florida, USA; Tómatelo a Pecho, A.C. (H.A-O., O.M., F.M.K.), Mexico City, Mexico; Sylvester Comprehensive Cancer Center, Miller School of Medicine (F.M.K.), University of Miami, Miami, Florida, USA; Leonard M. Miller School of Medicine (F.M.K.), University of Miami, Miami, Florida, USA
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5
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Shetty A, Saab EG, Choi G. Social Impact of Hepatic Encephalopathy. Clin Liver Dis 2024; 28:273-285. [PMID: 38548439 DOI: 10.1016/j.cld.2024.01.011] [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: 04/02/2024]
Abstract
Hepatic encephalopathy is a medical condition that stems from liver dysfunction, leading to the accumulation of toxins in the bloodstream. This can result in cognitive impairments, mood changes, and motor dysfunction. Its social impact includes challenges in employment, relationships, and daily functioning for affected individuals. Stigma and misunderstanding around the condition can further exacerbate the difficulties faced by both patients and their caregivers. Efforts to raise awareness, improve medical management, and provide support systems can help mitigate the social impact of hepatic encephalopathy.
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Affiliation(s)
- Akshay Shetty
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA; Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA.
| | - Elena G Saab
- School of Medicine, Wake Forest University, Winston Salem, NC, USA
| | - Gina Choi
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA; Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
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6
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Hjorth M, Svanberg A, LoMartire R, Kaminsky E, Rorsman F. Patient perceived quality of cirrhosis care- adjunctive nurse-based care versus standard medical care: a pragmatic multicentre randomised controlled study. BMC Nurs 2024; 23:251. [PMID: 38637755 PMCID: PMC11027520 DOI: 10.1186/s12912-024-01934-9] [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: 12/06/2023] [Accepted: 04/12/2024] [Indexed: 04/20/2024] Open
Abstract
BACKGROUND Cirrhosis treatment implies prevention and alleviation of serious disease events. Healthcare providers may, however, fail to meet patients' expectations of collaboration and specific needs of information and support. Individualised nursing care could meet patients' needs. The aim was thus to measure patient-perceived quality of care after adjunctive registered nurse-based intervention Quality Liver Nursing Care Model (QLiNCaM) compared with standard medical care. METHODS This pragmatic multicentre study consecutively randomised patients to either adjunctive registered nurse-based care, or standard medical care for 24 months (ClinicalTrials.gov NCT02957253). Patients were allocated to either group at an equal ratio, at six Swedish outpatient clinics during 2016-2022. Using the questionnaire 'Quality of care from the patient's perspective', patients rated their perceived lack of quality for the adjunctive registered nurse-based intervention compared with the control group at 12 and 24 months, respectively. RESULTS In total, 167 patients were recruited. Seven out of 22 items in the questionnaire supported the finding that 'lacking quality' decreased with adjunctive registered nurse-based care (p < 0.05) at 12 months follow-up; however, these differences could not be established at 24 months. CONCLUSION Additional structured registered nurse-based visits in the cirrhosis outpatient team provided support for improved patient-perceived quality of care during the first 12 months. Registered nurses increase patient involvement and present easy access to cirrhosis outpatient care. Patients express appreciation for personalised information. This study reinforces registered nurses' role in the outpatient cirrhosis team, optimising patient care in compensated and decompensated cirrhosis. TRIAL REGISTRATION Registered at Clinical Trials 18th of October 2016, [ https://www. CLINICALTRIALS gov ], registration number: NCT02957253.
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Affiliation(s)
- Maria Hjorth
- Centre for Clinical Research in Dalarna, Uppsala University, Falun, Sweden.
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
| | | | - Riccardo LoMartire
- Centre for Clinical Research in Dalarna, Uppsala University, Falun, Sweden
- School of Health and Wellfare, Dalarna University, Falun, Sweden
| | - Elenor Kaminsky
- Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
| | - Fredrik Rorsman
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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7
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Yang Y, Eguchi A, Mori C, Hashimoto K. Depression-like phenotypes in mice following common bile duct ligation: Insights into the gut-liver-brain axis via the vagus nerve. Neurobiol Dis 2024; 192:106433. [PMID: 38331354 DOI: 10.1016/j.nbd.2024.106433] [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] [Received: 01/13/2024] [Revised: 02/06/2024] [Accepted: 02/06/2024] [Indexed: 02/10/2024] Open
Abstract
Depression frequently occurs in patients with liver cirrhosis, yet the reasons for this correlation are not fully understood. Dysbiosis of gut microbiota has been implicated in depression through the gut-brain axis via the vagus nerve. This study explored the potential role of the gut-liver-brain axis via the vagus nerve in depression-like phenotypes in mice with liver cirrhosis. These mice underwent common bile duct ligation (CBDL), a method used to stimulate liver cirrhosis. To assess depression-like behaviors, behavioral tests were conducted 10 days following either sham or CBDL surgeries. The mice with CBDL displayed symptoms such as splenomegaly, elevated plasma levels of interleukin-6 and tumor necrosis factor-α, depression-like behaviors, decreased levels of synaptic proteins in the prefrontal cortex (PFC), disrupted gut microbiota balance, and changes in blood metabolites (or lipids). Additionally, there were positive or negative correlations between the relative abundance of microbiome and behavioral data or blood metabolites (or lipids). Significantly, these changes were reversed in CBDL mice by performing a subdiaphragmatic vagotomy. Intriguingly, depression-like phenotypes in mice with CBDL were improved after a single injection of arketamine, a new antidepressant. These results suggest that CBDL-induced depression-like phenotypes in mice are mediated through the gut-liver-brain axis via the subdiaphragmatic vagus nerve, and that arketamine might offer a new treatment approach for depression in liver cirrhosis patients.
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Affiliation(s)
- Yong Yang
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan; Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Akifumi Eguchi
- Department of Sustainable Health Science, Chiba University Center for Preventive Medical Sciences, Chiba 263-8522, Japan
| | - Chisato Mori
- Department of Sustainable Health Science, Chiba University Center for Preventive Medical Sciences, Chiba 263-8522, Japan; Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
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Rajpurohit S, Musunuri B, Mohan PB, Bhat G, Shetty S. Factors Affecting and Promoting Health-related Quality of Life in Patients With Liver Cirrhosis: An Underestimated Domain in Patient Care. J Clin Exp Hepatol 2024; 14:101264. [PMID: 38076365 PMCID: PMC10709188 DOI: 10.1016/j.jceh.2023.07.417] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 07/31/2023] [Indexed: 01/03/2025] Open
Abstract
Cirrhosis patients have poor health-related quality of life (HRQoL). To enhance medical care and therapeutic approaches, it is crucial to identify factors that alter HRQoL in patients with cirrhosis. The present study aims to identify the potential factors affecting and promoting HRQoL in patients with liver cirrhosis. Four databases were extensively searched, including PubMed, Scopus, Embase, and Google Scholar. All original articles with liver cirrhosis and factor-altering HRQoL were included. The present study showed that elderly age, female gender, low family income, low body mass index (BMI), presence of anxiety and depression, presence of cirrhosis complications including ascites, hepatic encephalopathy (HE), and abnormal endoscopic findings, high disease severity score, presence of sarcopenia, disturbed sleep pattern, muscle cramps, poor sexual health, and increased levels of bilirubin, prothrombin time, and albumin-bilirubin ratio were the significant factors associated with lower HRQoL scores. Meanwhile, physical exercise, liver transplant, stem cell therapy, mindfulness, and the use of probiotics, rifaximin, and lactulose were associated with increased HRQoL scores. The present study recommends more prospective or randomized control trials with interventions including health education, yoga, psychotherapy, and other potential factors promoting HRQoL in patients with liver cirrhosis. The present study also emphasizes that the treating physician should consider taking HRQoL into account when prescribing medical therapy.
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Affiliation(s)
- Siddheesh Rajpurohit
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Balaji Musunuri
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Pooja B. Mohan
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Ganesh Bhat
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shiran Shetty
- Department of Gastroenterology & Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
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9
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Narasimman M, Hernaez R, Cerda V, Lee M, Sood A, Yekkaluri S, Khan A, Quirk L, Liu Y, Kramer JR, Craddock Lee S, Murphy CC, Tiro JA, Singal AG. Hepatocellular carcinoma surveillance may be associated with potential psychological harms in patients with cirrhosis. Hepatology 2024; 79:107-117. [PMID: 37401857 DOI: 10.1097/hep.0000000000000528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/06/2023] [Indexed: 07/05/2023]
Abstract
BACKGROUND AND AIMS The value of HCC surveillance is determined by the balance between benefits and harms; however, no studies have enumerated psychological harms. APPROACH AND RESULTS We fielded surveys measuring psychological harms to patients with cirrhosis in a multicenter randomized trial of HCC surveillance outreach. All patients with positive or indeterminate surveillance results and matched patients with negative results were invited to complete surveys measuring (1) depression through the Patient Health Questionnaire-ninth version, (2) anxiety through State-Trait Anxiety Inventory, (3) HCC-specific worry through Psychological Consequences Questionnaire, and (4) decisional regret. Patients were classified into 4 groups: true positive (TP), false positive (FP), indeterminate, and true negative (TN). Multivariable longitudinal regression analysis using the generalized estimating equation method was performed to compare the means of measures across groups. We conducted 89 semistructured interviews in a subset of patients stratified by health system and test results. Of 2872 patients in the trial, 311 completed 1+ follow-up survey (63 FP, 77 indeterminate, 38 TP, and 133 TN). Moderate depression decreased in TN patients, increased in TP, and had intermittent but mild increases in those with FP and indeterminate results. High anxiety temporarily increased in patients with TP results but resolved over time and was stable in those with FP and indeterminate results. Decisional regret was low and did not differ across groups. In semistructured interviews, patients reported apprehension, anxiety, emotional distress, and coping related to HCC surveillance. CONCLUSIONS Psychological harms of HCC surveillance appear mild but differ by test result. Future research should determine the impact of psychological harms on the value of HCC surveillance programs.
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Affiliation(s)
- Manasa Narasimman
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Ruben Hernaez
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas, USA
| | - Vanessa Cerda
- Peter O'Donnell Jr. School of Public Health, Houston, Texas, USA
| | - MinJae Lee
- Peter O'Donnell Jr. School of Public Health, Houston, Texas, USA
| | - Anubha Sood
- Peter O'Donnell Jr. School of Public Health, Houston, Texas, USA
| | - Sruthi Yekkaluri
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Aisha Khan
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Lisa Quirk
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Yan Liu
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Jennifer R Kramer
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas, USA
| | | | - Caitlin C Murphy
- Peter O'Donnell Jr. School of Public Health, Houston, Texas, USA
| | - Jasmin A Tiro
- Peter O'Donnell Jr. School of Public Health, Houston, Texas, USA
| | - Amit G Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
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Moon AM, Kim HP, Jiang Y, Lupu G, Bissram JS, Barritt AS, Tapper EB. Systematic Review and Meta-Analysis on the Effects of Lactulose and Rifaximin on Patient-Reported Outcomes in Hepatic Encephalopathy. Am J Gastroenterol 2023; 118:284-293. [PMID: 36730910 PMCID: PMC9904367 DOI: 10.14309/ajg.0000000000002008] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/09/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Patients with hepatic encephalopathy (HE) suffer from significant symptoms and impaired quality of life. Improved understanding on the potential benefits of first-line HE therapies may aid patient-provider discussions regarding expected benefits of HE treatments. We aimed to perform a systematic review to assess the effects of lactulose and rifaximin on patient-reported outcomes (PROs). METHODS We searched MEDLINE, EMBASE, and Cochrane Library databases for randomized trials or prospective cohort studies using lactulose and/or rifaximin for the management of HE and assessing changes in PRO using PRO instruments. Physician reviewers independently reviewed titles, abstracts, and full texts and extracted data independently. We performed random-effects meta-analyses to examine the effects of lactulose and rifaximin on PROs. RESULTS We identified 16 studies representing 1,376 patients that met inclusion criteria. Most studies assessed treatment of covert HE. In patients with covert HE, lactulose significantly improved overall patient-reported health-related quality of life measured by the Sickness Impact Profile with an estimated pooled mean difference of 6.92 (95% confidence interval: 6.66-7.18) and showed improvements in several subscales. Conversely, rifaximin demonstrated a nonstatistically significant mean difference in the total Sickness Impact Profile of 4.76 (95% confidence interval: -4.23 to 13.76), with strong evidence of heterogeneity between these studies. Studies examining other PRO instruments showed improvements in overall health-related quality of life, social functioning, and sleep from both lactulose and rifaximin. DISCUSSION Patients with HE treated with lactulose or rifaximin reported improvements in important PROs. These results may inform provider-patient communication and help manage patient expectations regarding the potential benefits of HE therapies.
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Affiliation(s)
- Andrew M Moon
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Hannah P Kim
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Yue Jiang
- Department of Statistical Science, Duke University, Durham, North Carolina, USA
| | - Gabriel Lupu
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jennifer S Bissram
- Health Sciences Library, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - A Sidney Barritt
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
- Gastroenterology Section, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
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11
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Kong W, Sun X, Yu S, Liu P, Zheng X, Zhang J, Zhu L, Jiang T, Jin M, Gao J, Fan X, Liu X, Liu L. Bile duct ligation increased dopamine levels in the cerebral cortex of rats partly due to induction of tyrosine hydroxylase. Br J Pharmacol 2023. [PMID: 36692417 DOI: 10.1111/bph.16041] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 01/10/2023] [Accepted: 01/18/2023] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND AND PURPOSE Liver failure is associated with psychiatric alterations, partly resulting from the increased brain dopamine levels. We investigated the relationship between increased dopamine levels and mental abnormalities using bile duct ligation (BDL) rats and the mechanism by which liver failure increased dopamine levels in SH-SY5Y cells. Behavioural tests were carried out on day 13 and 27 following BDL, along with measurements of dopamine and metabolites, expressions of enzymes and transporters related to dopamine metabolism, and its transport into the cortex and the hippocampus. SH-SY5Y cells were used to investigate whether NH4 Cl, bile acids and bilirubin affected expression of tyrosine hydroxylase or not. Tyrosine hydroxylase (TH) expression in SH-SY5Y cells co-incubated with bilirubin and signal pathway inhibitors was measured. KEY RESULTS Open-field test results demonstrated BDL rats showed anxiety-like behaviour, accompanied by increased dopamine levels and expression of TH protein in the cortex. Membrane bound long form (MB)-COMT, slightly but significantly decreased. SH-SY5Y cells indicated that increased bilirubin levels was a factor in inducing TH expression. Both inhibitor of NF-κB pathway BAY 11-7082 and silencing NF-κB p65 reversed bilirubin-induced upregulation of TH protein. NF-κB activator TNF-α increased expression of TH protein. Roles of bilirubin in increases of TH protein expressions and dopamine levels were measured using hyperbilirubinemia rats. Anxiety-like behaviour, was associated with increased dopamine levels and TH protein expressions in hyperbilirubinemia rats. CONCLUSION AND IMPLICATIONS BDL significantly increased dopamine levels in rat cortex partly due to bilirubin-mediated TH induction. Increased bilirubin induced TH expression via activating NF-κB signalling pathway.
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Affiliation(s)
- Weimin Kong
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China.,School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu, Anhui, China
| | - Xueying Sun
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Siyu Yu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Peihua Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoke Zheng
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jiaxin Zhang
- Hunan Provincial People's Hospital (The first-affiliated hospital of Hunan Normal University), Changsha, China
| | - Liang Zhu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Tianxin Jiang
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Mengmeng Jin
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jinghui Gao
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaomin Fan
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaodong Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Li Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
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12
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Zang G, Sun X, Sun Y, Zhao Y, Dong Y, Pang K, Cheng P, Wang M, Zheng Y. Chronic liver diseases and erectile dysfunction. Front Public Health 2023; 10:1092353. [PMID: 36684968 PMCID: PMC9853559 DOI: 10.3389/fpubh.2022.1092353] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/19/2022] [Indexed: 01/07/2023] Open
Abstract
Chronic liver diseases (CLDs) are characterized by progressive necrosis of hepatocytes, which leads to liver fibrosis and cirrhosis, and ultimately liver dysfunction. The statistics of 2020 shows that the number of patients with CLDs, including chronic hepatitis, fatty liver, and cirrhosis, may exceed 447 million in China. The liver is a crucial organ for the metabolism of various substances, including sex hormones and lipids. CLDs frequently result in abnormalities in the metabolism of sex hormones, glucose, and lipids, as well as mental and psychological illnesses, all of which are significant risk factors for erectile dysfunction (ED). It has been reported that the prevalence of ED in male patients with CLDs ranges from 24.6 to 85.0%. According to a survey of Caucasians, liver transplantation may improve the erectile function of CLDs patients with ED. This finding supports the link between CLDs and ED. In addition, ED is often a precursor to a variety of chronic diseases. Given this correlation and the significant prevalence of CLDs, it is important to evaluate the epidemiology, risk factors, etiology, and treatment outcomes of ED in male patients with CLDs, expecting to attract widespread attention.
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Affiliation(s)
- Guanghui Zang
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Xv Sun
- Graduate School, Bengbu Medical College, Bengbu, Anhui, China
| | - Yufeng Sun
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Yan Zhao
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Yang Dong
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Kun Pang
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Ping Cheng
- Graduate School, Bengbu Medical College, Bengbu, Anhui, China
| | - Meng Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Yuli Zheng
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
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13
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Seo GH, Yoo JJ. Incidence of major depressive disorder over time in patients with liver cirrhosis: A nationwide population-based study in Korea. PLoS One 2022; 17:e0278924. [PMID: 36490257 PMCID: PMC9733842 DOI: 10.1371/journal.pone.0278924] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 11/23/2022] [Indexed: 12/13/2022] Open
Abstract
There is yet to be a large-scale longitudinal study on the course of depression incidence within the duration of cirrhosis. The aim of this study is to analyze the incidence of depression from before to after diagnosis of cirrhosis over time. Incidence Rate (IR) was defined as the number of newly diagnosed patients with MDD divided by the sum of observation periods by using claims database in Korea. Incidence Rate Ratio (IRR) was defined as the IR in the specific interest period divided by the IR in the control period. The control period was defied as 1 to 2 years before diagnosis of cirrhosis. The IRs before and after cirrhosis diagnosis were 3.56 and 7.54 per 100 person-year, respectively. The IRR was 2.12 (95% confidence Interval: 2.06-2.18). The IRR of developing depression mildly increased before diagnosis of cirrhosis (-360 days to -181 days, IRR 1.14, p < 0.001; -180 days to -90 days, IRR 1.24, p < 0.001; -90 days to -31 days, IRR 1.56, p < 0.001) and rapidly increased immediately after diagnosis of cirrhosis (+30 days to +89 days, IRR 2.12, 95% confidence interval: 2.06-2.18, p < 0.001). The pattern of increasing depression immediately after the diagnosis of cirrhosis was observed equally in all sexes and ages. Thus, clinicians must pay close attention to screening for depression within the first three months of liver cirrhosis diagnosis.
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Affiliation(s)
- Gi Hyeon Seo
- Health Insurance Review and Assessment Service, Wonju, South Korea
| | - Jeong-Ju Yoo
- Department of Gastroenterology and Hepatology, Soonchunhyang University School of Medicine, Bucheon, South Korea
- * E-mail:
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14
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Minimal Hepatic Encephalopathy Affects Daily Life of Cirrhotic Patients: A Viewpoint on Clinical Consequences and Therapeutic Opportunities. J Clin Med 2022; 11:jcm11237246. [PMID: 36498820 PMCID: PMC9736966 DOI: 10.3390/jcm11237246] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/27/2022] [Indexed: 12/12/2022] Open
Abstract
Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological testing focused on attention, working memory, psychomotor speed and visuospatial ability. Ideally, each patient should be tested for this condition because, despite the absence of symptoms, it has severe repercussions on daily life activities. It may be responsible for an inability to drive, sleep disturbances, risk of falls and inability to work. Some studies have highlighted its prognostically unfavorable role on mortality and risk of "overt" HE (OHE). Finally, MHE severely affects the lives of patients and caregivers, altering their quality of life and their socioeconomic status. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics, such as rifaximin, probiotics and branched-chain amino acids, with promising results. For this reason, early diagnosis and intervention with appropriate measures is essential, with the aim of improving both performance on psychometric tests, as well as clinical aspects related to this condition.
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15
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Whitsett MP, Goswami Banerjee A, Serper M. Assessment of mental health in patients with chronic liver disease. Clin Liver Dis (Hoboken) 2022; 20:52-56. [PMID: 36033429 PMCID: PMC9405502 DOI: 10.1002/cld.1214] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/21/2021] [Accepted: 01/19/2022] [Indexed: 02/04/2023] Open
Abstract
Content available: Audio Recording.
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Affiliation(s)
| | | | - Marina Serper
- Gastroenterology and HepatologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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16
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Anxiety in cirrhosis: a prospective study on prevalence and development of a practical screening nomogram. Eur J Gastroenterol Hepatol 2022; 34:553-559. [PMID: 35421020 DOI: 10.1097/meg.0000000000002301] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVES The prevalence and effects of anxiety on health-related quality of life and clinical outcomes in cirrhosis are not well understood. This is increasingly relevant during COVID-19. Our aim was to use the Mini-International Neuropsychiatric Interview (MINI) to determine the prevalence of anxiety, its association with clinical outcomes in cirrhosis and to develop a rapid cirrhosis-specific anxiety screening nomogram. METHODS Adults with a diagnosis of cirrhosis were prospectively recruited as outpatients at three tertiary care hospitals across Alberta and followed for up to 6 months to determine the association with unplanned hospitalization/death. The Hospital Anxiety and Depression scale (HADS) was used as a screening tool as it is free of influence from somatic symptoms. Anxiety was diagnosed using the MINI. RESULTS Of 304 patients, 17% of patients had anxiety by the MINI and 32% by the HADS. Anxious patients had lower health-related quality of life as assessed by the chronic liver disease questionnaire (P < 0.001) and EuroQol Visual Analogue Scale (P < 0.001), and also had higher levels of frailty using the Clinical Frailty score (P = 0.004). Multivariable analysis revealed smoking and three HADS subcomponents as independent predictors of anxiety. These were used to develop a rapid screening nomogram. CONCLUSION A formal diagnosis of anxiety was made in approximately one in five patients with cirrhosis, and it was associated with worse HrQoL and frailty. The use of a 4-question nonsomatic symptom-based nomogram requires validation but is promising as a rapid screen for anxiety in cirrhosis.
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17
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Kronsten VT, Tranah TH, Pariante C, Shawcross DL. Gut-derived systemic inflammation as a driver of depression in chronic liver disease. J Hepatol 2022; 76:665-680. [PMID: 34800610 DOI: 10.1016/j.jhep.2021.11.008] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/13/2021] [Accepted: 11/08/2021] [Indexed: 02/08/2023]
Abstract
Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction - a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well-documented in a cohort of patients with depression; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signalling, and peripheral immune cell-to-brain signalling. Gut dysbiosis has been observed in both patients with cirrhosis and depression. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for the treatment of depression in patients with cirrhosis.
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Affiliation(s)
- Victoria T Kronsten
- Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
| | - Thomas H Tranah
- Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Carmine Pariante
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT, UK
| | - Debbie L Shawcross
- Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK
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18
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Mason D, Happé F. The role of alexithymia and autistic traits in predicting quality of life in an online sample. RESEARCH IN AUTISM SPECTRUM DISORDERS 2022; 90:None. [PMID: 35116075 PMCID: PMC8763252 DOI: 10.1016/j.rasd.2021.101887] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 11/19/2021] [Accepted: 11/21/2021] [Indexed: 05/05/2023]
Abstract
BACKGROUND Autistic people tend to report poorer Quality of Life (QOL) than comparison groups, though some studies do report more optimistic findings. Higher autistic traits are also related to poorer QOL. However, the role of alexithymia in this relationship has not been explored. METHOD A total of 163 participants (N = 53 autistic and N = 111 comparison) consented to take part; however, 30 participants were excluded due to missing data (who did not differ from those who were retained on age, gender, education, employment, or living status), leaving a final sample of 133 (N = 42 Autistic and 91 Comparison participants). Demographic information (including age, gender) was collected, alongside self-report measures of autistic traits, mental health, alexithymia, and QOL. We estimated regression models based on pre-registered analysis, and we conducted exploratory network analyses. RESULTS Alexithymic traits did not predict QOL when controlling for covariates. Depression significantly predicted Physical, Psychological, and Social QOL. When examining the impact of just alexithymic traits and autistic traits, both were significantly associated with Physical and Psychological QOL. For participants with a low depression score, the correlation between alexithymia and QOL was strong; suggesting that depression occludes the association between alexithymia and QOL. Network analyses suggested that depression and anxiety exert direct effects on Physical and Psychological QOL, whereas alexithymia scores may influence Physical QOL via autistic traits. CONCLUSION In sum, depression is a pervasive negative predictor of multiple QOL domains. The role of alexithymia in predicting QOL dimensionally and categorically was not ruled out, given our exploratory analyses, we suggest that interventions which target alexithymia may positively impact QOL for those who score low on depressive symptoms.
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Affiliation(s)
- David Mason
- Social, Genetic and Developmental Psychiatry Centre, King’s College London, UK
| | - Francesca Happé
- Social, Genetic and Developmental Psychiatry Centre, King’s College London, UK
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19
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Hernaez R, Kramer JR, Khan A, Phillips J, McCallister K, Chaffin K, Hernandez AP, Fullington H, Ortiz C, Blackwell JM, Loewen A, Liu Y, Tiro JA, Lee SC, Singal AG. Depression and Anxiety Are Common Among Patients With Cirrhosis. Clin Gastroenterol Hepatol 2022; 20:194-203.e1. [PMID: 32835845 PMCID: PMC8210475 DOI: 10.1016/j.cgh.2020.08.045] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/07/2020] [Accepted: 08/16/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Depression and anxiety can have negative effects on patients and are important to treat. There have been few studies of their prevalence among patients with cirrhosis. We aimed to characterize the prevalence and risk factors for depression and anxiety in a large multi-center cohort of patients with cirrhosis. METHODS We conducted a telephone-based survey of patients with cirrhosis at 3 health systems in the United States (a tertiary-care referral center, a safety net system, and a Veterans hospital) from April through December 2018. Of 2871 patients approached, 1021 (35.6%) completed the survey. Depression and anxiety were assessed using the PHQ-9 (range 0-25) and STAI (range 20-80) instruments, with clinically significant values defined as PHQ-9 ≥15 and STAI ≥40. We performed multivariate logistic regression analysis to identify factors associated with significant depression and anxiety. RESULTS The median PHQ-9 score was 7 (25th percentile-75th percentile, 3-12) and the median STAI score was 33 (25th percentile-75th percentile, 23-47); 15.6% of patients had moderately severe to severe depression and 42.6% of patients had high anxiety. In multivariable analyses, self-reported poor health (odds ratio [OR], 4.08; 95% CI, 1.79-9.28), being widowed (OR, 2.08; 95% CI, 1.07-4.05), fear of hepatocellular carcinoma (OR, 1.89; 95% CI, 1.04-3.42), higher household income (OR, 0.30; 95% CI, 0.10-0.95), and Hispanic ethnicity (OR, 0.57; 95% CI, 0.33-0.97) were associated with moderately severe to severe depression. Male sex (OR, 0.71; 95% CI, 0.51-0.98), self-reported poor health (OR, 2.73; 95% CI, 1.73-4.32), and fear of hepatocellular carcinoma (OR, 2.24; 95% CI, 1.33-3.78) were associated with high anxiety. CONCLUSIONS Nearly 1 in 6 patients with cirrhosis have moderately severe to severe depression and nearly half have moderate-severe anxiety. Patients with cirrhosis should be evaluated for both of these disorders.
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Affiliation(s)
- Ruben Hernaez
- Section of Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
| | - Jennifer R Kramer
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Aisha Khan
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Jessica Phillips
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Katharine McCallister
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Kassie Chaffin
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Adriana Portela Hernandez
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Hannah Fullington
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Cynthia Ortiz
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | | | - Adam Loewen
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Yan Liu
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Jasmin A Tiro
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Simon C Lee
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Amit G Singal
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas; Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
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20
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Gairing SJ, Galle PR, Schattenberg JM, Kostev K, Labenz C. Portal Vein Thrombosis Is Associated with an Increased Incidence of Depression and Anxiety Disorders. J Clin Med 2021; 10:5689. [PMID: 34884391 PMCID: PMC8658138 DOI: 10.3390/jcm10235689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 11/26/2021] [Accepted: 11/30/2021] [Indexed: 11/25/2022] Open
Abstract
Portal vein thrombosis (PVT) is a severe disease that adversely affects patients' well-being. Data on the influence of PVT on the occurrence of depression or anxiety disorders are lacking. This study aimed to explore the impact of PVT on the incidence of depression and anxiety disorders diagnoses in a large German primary care cohort over a ten-year period. Patients with PVT were matched to non-PVT individuals by age, sex, yearly consultation frequency, index year and comorbidities in a 1:5 ratio. The primary outcome of the study was the incidence of depression and anxiety disorders. The relationship between PVT and both depression and anxiety disorders was investigated using Cox regression models. We compared 547 patients with PVT with 2735 matched individuals without PVT. Within 5 years of the index date, 17.4% of patients with PVT and 9.3% of non-PVT individuals were diagnosed with depression (p < 0.001). Anxiety disorders were diagnosed in 5.5% and 3.0% of patients with PVT and non-PVT individuals, respectively (p = 0.002). On regression analyses, PVT was positively associated with incident depression (HR 2.01, 95% CI 1.53-2.64, p < 0.001) as well as anxiety disorders (HR 2.16, 95% CI 1.35-3.46, p = 0.001). Regarding depression, this association remained significant in women as well as in men. There was no association between PVT and the incidence of anxiety disorders in women. In conclusion, PVT is associated with the development of depression and anxiety disorders. However, further prospective studies are needed to confirm our findings before definitive recommendations can be made.
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Affiliation(s)
- Simon Johannes Gairing
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany; (S.J.G.); (P.R.G.); (J.M.S.)
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany
| | - Peter Robert Galle
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany; (S.J.G.); (P.R.G.); (J.M.S.)
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany
| | - Jörn M. Schattenberg
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany; (S.J.G.); (P.R.G.); (J.M.S.)
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany
| | - Karel Kostev
- Epidemiology, IQVIA, 60549 Frankfurt am Main, Germany;
| | - Christian Labenz
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany; (S.J.G.); (P.R.G.); (J.M.S.)
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany
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21
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Abstract
OBJECTIVES Although patients with cirrhosis often experience debilitating symptoms, few are referred for palliative care. Frailty is increasingly incorporated in liver transplantation evaluation and has been associated with symptom burden in other populations. We hypothesized that frail patients with cirrhosis are highly symptomatic and thus are likely to benefit from palliative care. METHODS Patients with cirrhosis undergoing outpatient liver transplantation evaluation completed the Liver Frailty Index (grip strength, chair stands and balance) and a composite of validated measures including the Edmonton Symptom Assessment Scale, distress and quality of life (QOL) measures. RESULTS Of 233 patients (median age 61 years, 43% women), 22% were robust, 59% prefrail and 19% frail. Overall, 38% of patients reported ≥1 severe symptoms based on preestablished Edmonton Symptom Assessment Scale criteria. Higher frailty categories were associated with increased prevalence of pain, dyspnea, fatigue, nausea, poor appetite, drowsiness, depression and poor well-being (test for trend, all P < 0.05). Frail patients were also more likely to report psychological distress and poor QOL (all P < 0.01). In univariate analysis, each 0.5 increase in liver frailty index was associated with 44% increased odds of experiencing ≥1 severe symptoms [95% confidence interval (CI), 1.2-1.7, P < 0.001], which persisted (odds ratio, 1.3, 95% CI, 1.0-1.6, P = 0.004) even after adjusting for Model for End Stage Liver Disease-Sodium, ascites, hepatic encephalopathy and age. CONCLUSION In patients with cirrhosis, frailty is strongly associated with physical/psychological symptoms, including pain and depression and poor QOL. Frail patients with cirrhosis may benefit from palliative care co-management to address symptoms and improve QOL.
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22
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Wang P, Gao X, Liang M, Fang Y, Jia J, Tian J, Li Z, Qin X. Dose-Effect/Toxicity of Bupleuri Radix on Chronic Unpredictable Mild Stress and Normal Rats Based on Liver Metabolomics. Front Pharmacol 2021; 12:627451. [PMID: 34557088 PMCID: PMC8452938 DOI: 10.3389/fphar.2021.627451] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 08/24/2021] [Indexed: 01/23/2023] Open
Abstract
Depression, one of the most prevalent psychiatric diseases, affects the quality of life of millions of people. Studies have shown that the lower polar fraction of Bupleuri Radix (PBR) elicited therapeutic effects in chronic unpredictable mild stress (CUMS) rats. In contrast, comparatively mild liver injury was observed in normal rats administered a high PBR dose. It is essential to clarify the effective and safe dose of PBR and its dose-effect/toxicity relationship. In this study, we used the CUMS model to evaluate the effects and toxicities of PBR and to decipher the dose-effect/toxicity relationship and mechanism using the liver metabonomics combined with multivariate statistical analysis. In CUMS rats, PBR improved the depression-like behaviors including reduced body growth rate, anhedonia, and locomotor activities, and markedly reduced the contents of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In control rats, PBR treatment altered ALT and AST from typical levels. Moreover, the effective dose range for CUMS rats was 12.6–163 g (herb)/kg, the median toxicity dose for CUMS and normal rats were 388 and 207 g (herb)/kg. The toxicological results showed that the cytokeratin-18 fragment level was increased significantly in CUMS rats given with 100 g (herb)/kg PBR. After a comprehensive analysis, the use of PBR dose was determined to be 12.6–50 g (herb)/kg. In CUMS rats, PBR could reverse amino acid metabolism, energy metabolism, sphingolipid metabolism, and β-oxidation of fatty acids to produce an anti-depressant effect in a dose-dependent manner. In control rats, two additional metabolic pathways were significantly perturbed by PBR, including glycerophospholipid metabolism and bile acid metabolism. Moreover, the comprehensive metabolic index including dose-effect index (DEI) and dose toxicity index (DTI) had a remarkable ability (ROC = 0.912, ROC = 0.878) to predict effect and toxicity. The DEI and DTI were used to determine the dose range of effect and toxicity which was shown high concordance with previous results. Furthermore, the CUMS rats possessed a higher toxicity tolerance dose of PBR which was consistent with the theory of “You Gu Wu Yun” in traditional Chinese medicine. The metabonomics techniques combined with correlation analysis could be used to discover indicators for comprehensive evaluations of efficacy and toxicity.
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Affiliation(s)
- Peng Wang
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China
| | - Xiaoxia Gao
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China.,Key Laboratory of Chemical Biology and Molecular Engineering of Ministry Education of Shanxi University, Taiyuan, China
| | - Meili Liang
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China
| | - Yuan Fang
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China
| | - Jinping Jia
- Scientific Instrument Center, Shanxi University, Taiyuan, China
| | - Junsheng Tian
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China.,Key Laboratory of Chemical Biology and Molecular Engineering of Ministry Education of Shanxi University, Taiyuan, China
| | - Zhenyu Li
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China.,Key Laboratory of Chemical Biology and Molecular Engineering of Ministry Education of Shanxi University, Taiyuan, China
| | - Xuemei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China.,Key Laboratory of Chemical Biology and Molecular Engineering of Ministry Education of Shanxi University, Taiyuan, China
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23
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Faccioli J, Nardelli S, Gioia S, Riggio O, Ridola L. Neurological and psychiatric effects of hepatitis C virus infection. World J Gastroenterol 2021; 27:4846-4861. [PMID: 34447230 PMCID: PMC8371503 DOI: 10.3748/wjg.v27.i29.4846] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/07/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is widespread and affects 71 million people worldwide. Although hepatic manifestations are the most frequent, ranging from chronic hepatitis to cirrhosis and hepatocellular carcinoma, it is also associated with several extrahepatic manifestations. Infected patients may present non-specific neurological symptoms, regardless of the presence of liver cirrhosis. Several pathogenetic mechanisms underlying neurological symptoms have been hypothesized: neuroinvasion, immune-mediated damage, neurotransmitter alterations and cryoglobulinemia. Alterations of the central nervous system include cerebral vasculopathy, acute or subacute encephalopathy and inflammatory disorders. HCV infection may be responsible for neuropathies, of which the most frequent form is symmetrical axonal sensory or sensory-motor polyneuropathy which causes loss of leg sensitivity and weakness. Up to 50% of patients with HCV infection may experience cognitive decline and psychological disorders, such as depression and fatigue. HCV associated neurocognitive disorder is independent of the presence of liver cirrhosis and affects different domains than in patients with hepatic encephalopathy. It can be studied using specific tests that mainly explore executive functions, verbal learning and verbal recall. These disorders significantly reduce the quality of life. The new antiviral therapies improve the extrahepatic symptoms of HCV infection and their success depends on the achievement of sustained virological response. However, the effect of therapy may differ depending on the type of organ involved; neurological symptoms can be irreversible if there is organic liver damage. The aim of this review is to provide a critical overview of physiopathological mechanisms, diagnostic and therapeutic strategies of the neurological and psychiatric effects of HCV infection.
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Affiliation(s)
- Jessica Faccioli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Silvia Nardelli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Stefania Gioia
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Oliviero Riggio
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
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24
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Wang P, Gao X, Zhao F, Gao Y, Wang K, Tian JS, Li Z, Qin XM. Study of the Neurotransmitter Changes Adjusted by Circadian Rhythm in Depression Based on Liver Transcriptomics and Correlation Analysis. ACS Chem Neurosci 2021; 12:2151-2166. [PMID: 34060807 DOI: 10.1021/acschemneuro.1c00115] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Depression has drawn increasing attention from the public around the world in recent years. Studies have shown that liver injury caused by chronic stress is relevant to depression and neurotransmitter changes. It is essential to clarify the relationship between neurotransmitter changes and hepatic gene expression in depression. In this study, we used the chronic unpredictable mild stress (CUMS) model combined with UHPLC-MS to explore the changes of neurotransmitters in serum and hippocampus and to decipher the differential gene expression in the liver by using the RNA-Seq combined with multivariate statistical analysis. Compared with the control group, the levels of neurotransmitters including 5-hydroxytryptamine (5-HT), acetylcholine, glutamate (Glu), and dopamine (DA) in the hippocampus and 5-HT, norepinephrine, γ-aminobutyric acid (GABA), and 5-hydroxyindoleacetic acid in serum were significantly changed in the CUMS rats. The results of liver transcriptomic analysis and correlation analysis showed that the Glu, DA, 5-HT, and GABA were impacted by 68 liver genes which were mainly enriched in three pathways including circadian rhythm, serotonergic synapse, and p53 signaling pathway. The expressive levels of clock genes and serotonergic synapse genes were validated by using q-PCR, and the diurnal rhythms of neurotransmitters were validated by in vivo hippocampus microdialysis. The CUMS stressors might cause phase advance of Glu and GABA by adjusting clock genes. The transcriptomic technique combined with correlation analysis and in vivo microdialysis could be used to discover comprehensive pathways of depression. It provides a new strategy for the rational assessment of the mechanism of disease.
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Affiliation(s)
- Peng Wang
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
| | - Xiaoxia Gao
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
- Key Laboratory of Chemical Biology and Molecular Engineering of Ministry Education of Shanxi University, Taiyuan 030006, China
| | - Fang Zhao
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
- College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Yao Gao
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
| | - Kexin Wang
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
| | - Jun-Sheng Tian
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
- Key Laboratory of Chemical Biology and Molecular Engineering of Ministry Education of Shanxi University, Taiyuan 030006, China
| | - Zhenyu Li
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
- Key Laboratory of Chemical Biology and Molecular Engineering of Ministry Education of Shanxi University, Taiyuan 030006, China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
- Key Laboratory of Chemical Biology and Molecular Engineering of Ministry Education of Shanxi University, Taiyuan 030006, China
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25
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Liu XJ, Liu HL, Zhao D, Wei FX, Wang YZ, Lv M, Chen SJ, Li SY, Qin XM. Hepatic metabolomics of the compatibility effect of Xiaoyaosan on CUMS-induced depression based on the TCM theory of "Treating Diseases via Regulating the Liver's Function". J Pharm Biomed Anal 2021; 201:114123. [PMID: 33989991 DOI: 10.1016/j.jpba.2021.114123] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 02/07/2023]
Abstract
This study aimed to demonstrate the scientific connotations and compatibility effects of Xiaoyaosan (XYS) based on the theory of "Treating Diseases via Regulating the Liver's Function" by hepatic metabolomics. XYS was divided into two efficacy groups, i.e. the Shugan (SG) and the Jianpi (JP) groups, according to the strategy of "Efficacy Compositions". The chronic unpredictable mild stress (CUMS) depression model was constructed. A 1H NMR-based hepatic metabolomics approach coupled with multivariate data (MVD) analysis was performed. Meanwhile, relative distance (RD) and Efficacy Index (EI) were calculated. XYS and its efficacy groups significantly reversed the abnormality of behavior and hepatic metabolomics of depression rats, but to different degrees. The results of ethology and metabolomics showed the same order, i.e. XYS > JP > SG. Two metabolites, i.e. tyrosine and malate, were regulated by all the treatment groups. Four metabolites were significantly regulated only by XYS group. Of note, the results showed the two efficacy groups of XYS exhibited synergistic anti-depression effects, and glutamate, malate and taurine could be the key hepatic metabolites for these synergistic effects. The current study not only complements and consummates the mechanisms of depression and the anti-depression effects of XYS from the perspective of hepatic metabolomics, but also lays a solid foundation for comprehensively and deeply understanding the compatibility effects of XYS against depression, especially from the points of view of compatibility in Traditional Chinese medicine (TCM) theory and synergism in modern medicine theory.
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Affiliation(s)
- Xiao-Jie Liu
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Effective Substances Research and Utilization in Traditional Chinese Medicine of Shanxi Province, Taiyuan, 030006, China.
| | - Huan-le Liu
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Effective Substances Research and Utilization in Traditional Chinese Medicine of Shanxi Province, Taiyuan, 030006, China
| | - Di Zhao
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Effective Substances Research and Utilization in Traditional Chinese Medicine of Shanxi Province, Taiyuan, 030006, China
| | - Fu-Xiao Wei
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Effective Substances Research and Utilization in Traditional Chinese Medicine of Shanxi Province, Taiyuan, 030006, China
| | - Ya-Ze Wang
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Effective Substances Research and Utilization in Traditional Chinese Medicine of Shanxi Province, Taiyuan, 030006, China
| | - Meng Lv
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Effective Substances Research and Utilization in Traditional Chinese Medicine of Shanxi Province, Taiyuan, 030006, China
| | - Shi-Jian Chen
- School of Computer and Information Technology, Shanxi University, Taiyuan, 030006, China
| | - Shun-Yong Li
- School of Mathematics Sciences, Shanxi University, Taiyuan, 030006, China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, China; Key Laboratory of Effective Substances Research and Utilization in Traditional Chinese Medicine of Shanxi Province, Taiyuan, 030006, China.
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26
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Kedia SK, Ali B, Jiang Y, Arshad H, Satapathy SK, Gonzalez HC. Post-liver transplant outcomes in patients with major psychiatric diagnosis in the United States. Ann Hepatol 2021; 22:100311. [PMID: 33482365 DOI: 10.1016/j.aohep.2021.100311] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/01/2020] [Accepted: 12/11/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION AND OBJECTIVES Higher rates of psychiatric disorders are reported among cirrhotic patients. This study examines the demographic and clinical outcomes post-liver transplant (LT) among cirrhotic patients with a major psychiatric diagnosis (cases) compared to those without psychiatric diagnosis (controls). MATERIALS AND METHODS Retrospective case control design was used among 189 cirrhotic patients who had undergone LT at Methodist University Hospital Transplant Institute, Memphis, TN between January 2006 and December 2014. Multivariable regression and Cox proportional hazard regression were conducted to compare allograft loss and all-cause mortality. RESULTS The study sample consisted of a matched cohort of 95 cases and 94 controls with LT. Females and those with Hepatic Encephalopathy (HE) were more likely to have psychiatric diagnosis. Patients with hepatocellular carcinoma (HCC) were twice as likely to have allograft loss. Psychiatric patients with HCC had two and a half times (HR 2.54; 95% CI: 1.20-5.37; p = 0.015) likelihood of all-cause mortality. Data censored at 1-year post-LT revealed that patients with psychiatric diagnosis have a three to four times higher hazard for allograft loss and all-cause mortality compared to controls after adjusting for covariates, whereas when the data is censored at 5 year, allograft loss and all-cause mortality have two times higher hazard ratio. CONCLUSIONS The Cox proportional hazard regression analysis of censored data at 1 and 5 year indicate higher allograft loss and all-cause mortality among LT patients with psychiatric diagnosis. Patients with well-controlled psychiatric disorders who undergo LT need close monitoring and medication adherence.
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Affiliation(s)
- Satish K Kedia
- School of Public Health, University of Memphis, Memphis, TN, United States.
| | - Bilal Ali
- James D Eason Transplant Institute, Methodist University Hospital, University of Tennessee Health Science Center, Memphis, TN, United States.
| | - Yu Jiang
- School of Public Health, University of Memphis, Memphis, TN, United States.
| | - Hassan Arshad
- School of Public Health, University of Memphis, Memphis, TN, United States.
| | - Sanjaya K Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases & Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Manhasset, NY, United States.
| | - Humberto C Gonzalez
- Department of Gastroenterology and Hepatology, Henry Ford Health System, Detroit, MI, United States; Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, United States.
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27
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Housman B, Flores R, Lee DS. Narrative review of anxiety and depression in patients with esophageal cancer: underappreciated and undertreated. J Thorac Dis 2021; 13:3160-3170. [PMID: 34164206 PMCID: PMC8182527 DOI: 10.21037/jtd-20-3529] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Depression and anxiety are emotional disorders that commonly affect patients with esophageal cancer. As a result of its high morbidity, mortality, and complication rates, this population is at particularly high risk for developing or exacerbating affective disorders; even when compared to patients with other forms of cancer. Many of the medical conditions and social behaviors that predispose patients to this disease are also independently associated with affective disorders, and likely compound their effects. Unfortunately, in the existing literature, there is wide variability in study design and diagnostic criteria. There is no standard method of evaluation, many studies are limited to written surveys, and widespread mental health screening is not included as a part of routine care. As a result, the prevalence of these illnesses remains elusive. Additionally, psychiatric and psychosocial illness can affect compliance with surveillance and treatment, and gaps in knowledge may ultimately influence patient outcomes and survival. This review will discuss the existing literature on depression and anxiety in patients with esophageal cancer. It will highlight current methods of psychological evaluation, the prevalence of affective disorders in this population, and their effects on treatment, compliance, and outcomes. It will also discuss possible screening tools, treatments and interventions for these comorbid illnesses that may improve oncologic outcomes as well as quality of life.
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Affiliation(s)
- Brian Housman
- Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA
| | - Raja Flores
- Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA
| | - Dong-Seok Lee
- Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA
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28
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Gray-Renfrew A, Kimbell B, Finucane A. Emotional experience of people with advanced liver disease: Secondary data analysis. Chronic Illn 2020; 16:284-295. [PMID: 30286621 DOI: 10.1177/1742395318803668] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Patients with advanced liver disease live mainly in the community with treatment of complications provided for in-hospital. The illness trajectory of advanced liver disease is uncertain and most do not have access to end of life care. Gaps in knowledge and understanding of the patient experience of this condition have been identified. METHODS Secondary analysis of 15 transcripts from in-depth interviews with people with advanced liver disease collected as part of a previous longitudinal study on the experience of liver disease. Transcripts were thematically analysed for emotional content. RESULTS Fear, anger, sadness and guilt clearly featured in the person's experience of advanced liver disease. Certain causal factors were identified as provoking these emotional responses, including shock of diagnosis, uncertainty concerning illness, lack of coordinated care, worrying symptoms and sudden death. Humour emerged as a coping mechanism. CONCLUSION People living with advanced liver disease experience distressing emotions. It is helpful for clinicians, nurses and other healthcare support staff to have an appreciation of the person's emotional concerns in order to provide holistic care typical of a palliative approach.
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Affiliation(s)
| | - Barbara Kimbell
- Primary Palliative Care Research Group, Centre for Population Health Sciences, University of Edinburgh, Scotland, UK
| | - Anne Finucane
- Marie Curie Hospice Edinburgh, Usher Institute, University of Edinburgh, Scotland, UK
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29
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Late-onset depression is associated to age-related central auditory processing disorder in an older population in Southern Italy. GeroScience 2020; 43:1003-1014. [PMID: 33128133 PMCID: PMC8110676 DOI: 10.1007/s11357-020-00290-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 10/15/2020] [Indexed: 01/16/2023] Open
Abstract
The association between late-life depression (LLD) and age-related hearing loss (ARHL) was suggested by preliminary studies, but reliance on LLD subtypes may introduce significant bias. We examined the association between ARHL and LLD according to the age of onset (early-onset depression (EOD) and late-onset depression (LOD)). We investigated the association between ARHL and LLD diagnosed according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR in 1749 Italian community-dwelling older subjects from the population-based GreatAGE Study, Southern Italy. Peripheral ARHL was assessed as a pure tone average (PTA) threshold > 40 dB hearing level in the better ear- and age-related CAPD as a score of < 50% to the Synthetic Sentences Identification with Ipsilateral Competitive Message (SSI-ICM) test. LLD amounted at 10.29% of the sample, subdivided in LOD (6.21%) and EOD (4.08%). Age-related CAPD tended to be higher in LOD (28.91%) than in EOD (19.05%). After accounting for covariates, LOD was tendentially associated to age-related CAPD, but not to peripheral ARHL. This trend was confirmed by the linear models in which LOD was significantly associated to worsen SSI-ICM percentages (odds ratio 2.38, 95% confidence interval 1.32-4.30, p = 0.004), but not to PTA values. In a fully adjusted model of LOD, the effect of the association between CAPD and LOD was explained by social dysfunction. LLD was not associated to peripheral ARHL. Age-related CAPD was associated to LOD, a form of depression with cognitive dysfunction hallmark. The ARHL assessment may be an important opportunity to prevent depressive disorders in later life, particularly for LOD.
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30
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Rogal SS, Yakovchenko V, Gonzalez R, Park A, Lamorte C, Gibson SP, Chartier M, Ross D, Comstock E, Bajaj JS, Morgan TR. Characterizing patient-reported outcomes in veterans with cirrhosis. PLoS One 2020; 15:e0238712. [PMID: 32915828 PMCID: PMC7485762 DOI: 10.1371/journal.pone.0238712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/21/2020] [Indexed: 02/08/2023] Open
Abstract
Background and aims The Veterans Health Administration (VA) cares for over 80,000 Veterans with cirrhosis annually. Given the importance of understanding patient reported outcomes in this complex population, we aimed to assess the associations between attitudes towards care, disease knowledge, and health related quality of life (HRQoL) in a national sample. Methods In this cross-sectional study, we mailed paper surveys to a random sample of Veterans with cirrhosis, oversampling those with decompensated disease. Surveys included the Veterans RAND 12-Item Health Survey (measuring HRQoL) and questions about demographics, characteristics of care, satisfaction with care (“attitudes towards care”), and symptoms of cirrhosis. Those who reported being “unsure” about whether they had decompensation events were defined as “unsure about cirrhosis symptoms” (“disease knowledge”). We used multivariable regression models to assess the factors associated with HRQoL. Results Of 1374 surveys, 551 (40%) completed surveys were included for analysis. Most Veterans (63%) were “satisfied” or “very satisfied” with VA liver care. Patients often self-reported being unsure about whether they had experienced hepatic decompensation events (34%). Overall average physical (PCS) and mental (MCS) component scores of HRQoL were 30±11 and 41±12. In multivariable regression models, hepatic decompensation (PCS:β = -3.8, MCS:β = -2.2), medical comorbidities (β = −-2.0, β = -1.7), and being unsure about cirrhosis symptoms (β = -1.9, β = -3.3) were associated with worse HRQoL, while age (β = 0.1, β = 0.2) and satisfaction with care (β = 0.6; β = 1.6) were associated with significantly better HRQoL. Conclusions Hepatic decompensation, lower satisfaction with care, and being unsure about cirrhosis symptoms were associated with reduced QOL scores in this national cohort.
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Affiliation(s)
- Shari S. Rogal
- Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, United States of America
- Departments of Medicine and Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- * E-mail: ,
| | - Vera Yakovchenko
- Center for Healthcare Organization and Implementation Research, Edith Norse Rogers Memorial VA Hospital, Bedford, Massachusetts, United States of America
| | - Rachel Gonzalez
- Gastroenterology Section, VA Long Beach Healthcare System, Long Beach, California, United States of America
| | - Angela Park
- Department of Veterans Affairs, Office of Healthcare Transformation, Washington, DC, United States of America
| | - Carolyn Lamorte
- Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, United States of America
| | - Sandra P. Gibson
- Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, United States of America
| | - Maggie Chartier
- Veterans Health Administration, HIV, Hepatitis, and Related Conditions Programs, Office of Specialty Care Services, Washington, DC, United States of America
| | - David Ross
- Veterans Health Administration, HIV, Hepatitis, and Related Conditions Programs, Office of Specialty Care Services, Washington, DC, United States of America
| | - Emily Comstock
- Department of Infectious Diseases, Baltimore VA Medical Center, Baltimore, Maryland, United States of America
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Division of Gastroenterology, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia, United States of America
| | - Timothy R. Morgan
- Gastroenterology Section, VA Long Beach Healthcare System, Long Beach, California, United States of America
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Wang B, Lu S, Zhang C, Zhu L, Li Y, Bai M, Xu E. Quantitative proteomic analysis of the liver reveals antidepressant potential protein targets of Sinisan in a mouse CUMS model of depression. Biomed Pharmacother 2020; 130:110565. [PMID: 32745909 DOI: 10.1016/j.biopha.2020.110565] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/17/2020] [Accepted: 07/26/2020] [Indexed: 12/12/2022] Open
Abstract
In traditional Chinese medicine, the role of the liver in depression is highly valued, and liver-relieving drugs, such as Sinisan, are often used to treat depression; however, the mechanism whereby these drugs work remains unclear. The present study aimed to reveal possible antidepressant mechanisms of Sinisan (SNS) by analyzing hepatic proteomics in chronic unpredictable mild stress (CUMS) mice. Using the CUMS mouse model of depression, the antidepressant effects of SNS were assessed by the sucrose preference test (SPT) and forced swimming test (FST). Hepatic differentially expressed proteins (DEPs) after SNS treatment were investigated by tandem mass tag (TMT) based quantitative proteomics analysis. Then, a bioinformatics analysis of DEPs was conducted through hierarchical clustering, Venn analysis, Gene Ontology (GO) annotation enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. DEP genes were further validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis and western blotting. Behavioral results demonstrated that SNS significantly increased sucrose intake in SPT and shortened the immobility time in FST in model mice. Eighty-two DEPs were identified, including 37 upregulated and 45 downregulated proteins, between model and SNS groups. Enrichment analysis of GO annotations indicated that SNS primarily maintained cellular iron ion homeostasis by iron ion transportation and regulated expression of some extracellular structural proteins for oxidation-reduction processes. KEGG and Venn analysis showed that mineral absorption, steroid hormone biosynthesis and metabolism might be the principal pathways through which SNS acts on depression. Furthermore, several proteins involved in the biosynthesis and metabolism of steroid hormone pathways were significantly up/downregulated by SNS, including CYP2B19, CYP7B1 (validated by qRT-PCR) and HSD3b5 (validated by qRT-PCR and western blotting). Our results indicate that SNS plays important roles in antidepressant actions by restoring DEPs, resulting in the biosynthesis and metabolism of steroid hormones. The current results provide novel perspectives for revealing potential protein targets of SNS in depression.
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Affiliation(s)
- Baoying Wang
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, China.
| | - Shuaifei Lu
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Changjing Zhang
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Leilei Zhu
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Yucheng Li
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Ming Bai
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, China.
| | - Erping Xu
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, China.
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Chen C, Yin Q, Tian J, Gao X, Qin X, Du G, Zhou Y. Studies on the potential link between antidepressant effect of Xiaoyao San and its pharmacological activity of hepatoprotection based on multi-platform metabolomics. JOURNAL OF ETHNOPHARMACOLOGY 2020; 249:112432. [PMID: 31790818 DOI: 10.1016/j.jep.2019.112432] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 05/22/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In traditional Chinese medicine (TCM) theory, depression is considered to be "liver qi stagnation", and relieving "liver qi stagnation" is regarded as an effective method for treating depression. Xiaoyao San (XYS) is a well-known TCM formula for the treatment of depression by relieving "liver qi stagnation". This formula consists of Radix Paeoniae Alba (Paeonia lactiflora Pall.), Radix Bupleuri (Bupleurum chinense DC.), Poria (Poria cocos (Schw.) Wolf), Rhizoma Atractylodis Macrocephalae (Atractylodes macrocephala Koidz.), Radix Angelicae Sinensis (Angelica sinensis (Oliv.) Diels), Radix Glycyrrhizae (Glycyrrhiza uralensis Fisch.), Rhizoma Zingiberis Recens (Zingiber officinale Roscoe) and Herba Menthae Haplocalycis (Mentha haplocalyx Briq.). AIM OF THE STUDY Several studies have suggested that depression is associated with liver injury. XYS was a well-known TCM formula for the treatment of depression and liver stagnancy. However, it was still unknown whether the antidepressant effect of XYS is related to the pharmacological activity of hepatoprotection. The aim of this study was to elucidate the potential link between the antidepressant and hepatoprotective effect of XYS. MATERIALS AND METHODS A depression rat model was established by the CUMS (chronic unpredictable mild stress) procedure. The antidepressant effect of XYS was assessed by the behavioral indicators, and the hepatoprotective effect of XYS was evaluated through biochemical assays. 1H-NMR and LC/MS-based liver metabolomics were performed to discover key metabolic pathways involved in the antidepressant and hepatoprotective effects of XYS. Further, the key pathway was validated using commercial kits. RESULTS The results demonstrated that XYS pretreatment could significantly improve the depressive symptom induced by CUMS. More importantly, the results demonstrated that liver injury was observed in the CUMS model rats, and XYS had a hepatoprotective effect by reducing the activities of AST and ALT in serum, increasing the levels of SOD and GSH-Px and reducing the contents of MDA, IL-6, and IL-1β in the liver. In addition, the NMR and LC/MS-based metabolomics results indicated that XYS improved 23 of the 35 perturbed potential liver biomarkers that were induced by CUMS. Among them, 9 biomarkers were significantly correlated with both depression and liver pathology, according to Pearson correlation analysis. Metabolic pathway analyses of these 9 biomarkers showed that glutamine and glutamate metabolism were the most important metabolic pathways. Furthermore, to verify glutamine and glutamate metabolism, the levels of glutamine and glutamate, and the activity of glutamine synthetase (GS) and glutaminase (GLS) were quantitatively determined in the liver by commercial kits, and these results were consistent with the metabolomics results. CONCLUSIONS XYS could significantly improve the depressive and liver injury symptoms induced by CUMS. The metabolomics results indicate that the regulation of glutamine and glutamate metabolism to maintain the balance of ammonia and promote energy metabolism is a potential junction between the antidepressant and hepatoprotective effects of XYS.
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Affiliation(s)
- Congcong Chen
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan, 030006, PR China; College of Chemistry and Chemical Engineering, Shanxi University, No. 92, Wucheng Road, Taiyuan, 030006, PR China
| | - Qicai Yin
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan, 030006, PR China; College of Chemistry and Chemical Engineering, Shanxi University, No. 92, Wucheng Road, Taiyuan, 030006, PR China
| | - Junshen Tian
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan, 030006, PR China
| | - Xiaoxia Gao
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan, 030006, PR China
| | - Xuemei Qin
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan, 030006, PR China
| | - Guanhua Du
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan, 030006, PR China; Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, PR China
| | - Yuzhi Zhou
- Modern Research Center for Traditional Chinese Medicine of Shanxi University, No.92, Wucheng Road, Taiyuan, 030006, PR China.
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Eftekar M. The association between hepatic encephalopathy/minimal hepatic encephalopathy and depressive and anxiety disorders: a systematic review. Australas Psychiatry 2020; 28:61-65. [PMID: 31868516 DOI: 10.1177/1039856219875054] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES This review examined the currently available evidence of the association between liver encephalopathy and mood/anxiety disorders. METHOD English-language studies using the keywords "hepatic encephalopathy," "depression," and "anxiety" were searched through PubMed, Medline, Cochrane Library, and PsycINFO databases. A total of 135 articles were considered for this review, of which 9 were qualitative and quantitative research papers regarding depression and anxiety in hepatic encephalopathy (HE). RESULTS There is a significant discrepancy between the research method of the studies and their outcomes. The number of studies suggesting a relationship between HE and mood/anxiety disorders is slightly higher than that of studies with opposite results; however, based on the current evidence, it is difficult to conclude a significant association between these two conditions. CONCLUSION More longitudinal studies that include face-to-face psychiatric assessments are required to highlight any possible association between depressive/anxiety disorders and HE.
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Nardelli S, Riggio O, Rosati D, Gioia S, Farcomeni A, Ridola L. Hepatitis C virus eradication with directly acting antivirals improves health-related quality of life and psychological symptoms. World J Gastroenterol 2019; 25:6928-6938. [PMID: 31908396 PMCID: PMC6938730 DOI: 10.3748/wjg.v25.i48.6928] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/13/2019] [Accepted: 12/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alterations in health-related quality of life (HRQoL) and neuropsychological disorders were described in the hepatitis C virus (HCV) patients. Although several studies investigated the modifications of HRQoL after HCV eradication, no data exists on the modifications of neuropsychological symptoms. AIM To investigate the effect of directly acting antivirals (DAAs) treatment on HRQoL and neuropsychological symptoms. METHODS Thirty nine patients with HCV infection underwent a neuropsychological assessment, including Zung-Self Depression-Rating-Scale, Spielberg State-Trait Anxiety Inventory Y1-Y2 and the Toronto-Alexithymia Scale-20 items before and after DAAs treatment. HRQoL was detected by Short-Form-36 (SF-36). RESULTS All HRQoL domains, but role limitation physical and bodily pain, significantly improved after treatment. Interestingly, after DAAs treatment, all domains of HRQoL returned similar to those of controls. Each neuropsychological test significantly improved after HCV eradication. A significant correlation was observed among each psychological test and the summary components of SF-36. At multiple linear regression analysis including each psychological test as possible covariates, Zung-Self Depression Rating Scale (Zung-SDS) score was independently and significantly related to summary components of the SF-36 in the basal state and the difference between Zung-SDS score before and after treatment was the only variable significantly and independently related to the modification of HRQoL induced by the treatment. CONCLUSION Neuropsychological symptoms strongly influenced HRQoL in HCV patients and there was a significant improvement of neuropsychological tests and HRQoL after DAAs treatment.
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Affiliation(s)
- Silvia Nardelli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Oliviero Riggio
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Davide Rosati
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Stefania Gioia
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Alessio Farcomeni
- Department of Economics & Finance, University of Rome “Tor Vergata”, Rome 00185, Italy
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
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Nardelli S, Gioia S, Ridola L, Farcomeni A, Merli M, Riggio O. Proton Pump Inhibitors Are Associated With Minimal and Overt Hepatic Encephalopathy and Increased Mortality in Patients With Cirrhosis. Hepatology 2019; 70:640-649. [PMID: 30289992 DOI: 10.1002/hep.30304] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/02/2018] [Indexed: 12/12/2022]
Abstract
Minimal hepatic encephalopathy (MHE) is a subclinical cognitive impairment frequently observable in patients with cirrhosis. Proton pump inhibitors (PPIs) can contribute to small-bowel bacterial overgrowth, but no study has investigated the link between PPIs and MHE. We investigated the relationship between MHE and PPI use as well as the role of PPI use in the development of overt HE and survival. Consecutive patients with cirrhosis (n = 310) were included in the study and followed up for 14.1 ± 12.3 months. At entry, MHE was diagnosed when the Psychometric Hepatic Encephalopathy Score was ≤-4. Data were analyzed by logistic regression for the factors associated with MHE and by time-related models for overt HE development and survival. At inclusion, 131 out of 310 patients with cirrhosis (42%) were affected by MHE. One hundred and twenty-five patients (40%) were using PPIs. The variables independently associated with the presence of MHE were PPI use, previous overt HE, low albumin, low sodium, and age. During follow-up, the development of overt HE was higher (64% versus 25%, P < 0.001) and overall survival lower (41% versus 81%, P < 0.001) in PPI users than in nonusers. Variables independently associated with the development of overt HE were PPIs, history of overt HE, low albumin, MHE, and age, while variables independently associated with mortality were PPIs, development of overt HE, Model for End-Stage Liver Disease score, low sodium, and age. Conclusion: The study identifies a potentially removable factor associated with the presence of MHE and related to the development of overt HE and survival in patients with liver cirrhosis.
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Affiliation(s)
- Silvia Nardelli
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Stefania Gioia
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Alessio Farcomeni
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Rome, Italy
| | - Manuela Merli
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Oliviero Riggio
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
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Cho J, Walia M, Scragg R, Petrov MS. Frequency and risk factors for mental disorders following pancreatitis: a nationwide cohort study. Curr Med Res Opin 2019; 35:1157-1164. [PMID: 30614299 DOI: 10.1080/03007995.2018.1560748] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Objective: To investigate the frequency and risk factors for mental disorders following pancreatitis. Methods: Patients with acute pancreatitis (AP) and chronic pancreatitis (CP) were identified (n = 18,074) from a nationwide database in New Zealand (1998-2015). They were followed from their first hospital admissions for AP or CP to incident mental disorders. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression analyses. Results: CP (vs AP) was associated with a significantly higher risk of mental disorders (adjusted HR = 2.00 [95% CI = 1.53-2.62]). Pre-existing diabetes (adjusted HR = 8.99 [95% CI = 6.23-12.96] for AP and adjusted HR = 3.42 [95% CI = 2.37-4.96] for CP) and post-pancreatitis diabetes mellitus (adjusted HR = 7.10 [95% CI = 4.14-12.19] for AP and adjusted HR = 2.97 [95% CI = 1.83-4.82] for CP) were risk factors for mental disorders in individuals following pancreatitis. Severe (adjusted HR = 2.07 [95% CI = 1.39-3.06] vs mild) and recurrent (adjusted HR = 1.62 [95% CI = 1.07-2.45] vs single episode) attacks were associated with significantly higher risks of mental disorders following AP. Conclusions: Patients following CP, recurrent AP, severe AP, and those with diabetes are at high risk for developing mental disorders.
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Affiliation(s)
- Jaelim Cho
- a School of Medicine , University of Auckland , Auckland , New Zealand
| | - Monika Walia
- a School of Medicine , University of Auckland , Auckland , New Zealand
| | - Robert Scragg
- b School of Population Health , University of Auckland , Auckland , New Zealand
| | - Maxim S Petrov
- a School of Medicine , University of Auckland , Auckland , New Zealand
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Esteban JPG, Rein L, Szabo A, Saeian K, Rhodes M, Marks S. Attitudes of Liver and Palliative Care Clinicians toward Specialist Palliative Care Consultation for Patients with End-Stage Liver Disease. J Palliat Med 2019; 22:804-813. [DOI: 10.1089/jpm.2018.0553] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
| | - Lisa Rein
- Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Aniko Szabo
- Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Kia Saeian
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Mary Rhodes
- Section of Palliative Care, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Sean Marks
- Section of Palliative Care, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Neurocognitive impairment is associated with erectile dysfunction in cirrhotic patients. Dig Liver Dis 2019; 51:850-855. [PMID: 31031175 DOI: 10.1016/j.dld.2019.03.030] [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: 03/16/2018] [Revised: 03/27/2019] [Accepted: 03/27/2019] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Erectile dysfunction (ED) is common in patients with chronic diseases. It is evaluated using the International Index of Erectile Function (IIEF5) questionnaire. The relationship between ED and cirrhosis is complex. The aims of our study were (1) to assess the prevalence of ED in cirrhosis and (2) to evaluate factors associated with ED, with a special focus on minimal hepatic encephalopathy (MHE). METHODS We performed a prospective, observational study. Patients with cirrhosis were invited to complete the IIEF5 questionnaire. The exclusion criteria were clinical hepatic encephalopathy (HE) and dementia. MHE was evaluated by the psychometric hepatic encephalopathy test score (PHES) and the critical flicker frequency (CFF). RESULTS Between April 2016 and April 2017, 87 patients were included (age: 55 [51-57] years, Child-Pugh score: 8 [7-9], MELD score: 13 [11-16]. Minimal HE was diagnosed in 33% of the patients according to the PHES and in 44% of the patients according to the CFF. ED was diagnosed in 74/87 patients (85%) when compared to 12.5% in healthy controls (p < 0.001). In a multivariate analysis, the independent factors associated with ED were age, Child-Pugh and MELD scores. Significant correlations were identified between the IIEF5 and each component of the PHES. CONCLUSION ED should be systematically screened in cirrhotics, especially in patients with MHE.
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Riggio O, Ridola L, Gioia S, Nardelli S. Erectile dysfunction in patients with liver cirrhosis. Dig Liver Dis 2019; 51:856-857. [PMID: 31129135 DOI: 10.1016/j.dld.2019.05.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 05/02/2019] [Accepted: 05/06/2019] [Indexed: 12/11/2022]
Affiliation(s)
- O Riggio
- Dept. of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
| | - L Ridola
- Dept. of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
| | - S Gioia
- Dept. of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
| | - S Nardelli
- Dept. of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy.
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Ammonium induced dysfunction of 5-HT 2B receptor in astrocytes. Neurochem Int 2019; 129:104479. [PMID: 31145970 DOI: 10.1016/j.neuint.2019.104479] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 05/24/2019] [Accepted: 05/26/2019] [Indexed: 11/24/2022]
Abstract
Previously we reported that gene expression of astrocytic 5-HT2B receptors was decreased in brains of depressed animals exposed to chronic mild stress (CMS) (Li et al., 2012) and of Parkinson's disease (Song et al., 2018). Depression is also one of the psychiatric symptoms in hyperammonemia, and astrocyte is a primary target of ammonium in brain in vivo. In the present study, we have used preparations of the brains of urease-treated mice and ammonium-treated astrocytes in culture to study gene expression and function of 5-HT2B receptors. The urease-treated mice showed depressive behaviour. Both mRNA and protein of 5-HT2B receptors were increased in the brains of urease-treated mice and in ammonium-treated cultured astrocytes. Further study revealed that mRNA and protein expression of adenosine deaminase acting on RNA 2 (ADAR2), an enzyme catalyze RNA deamination of adenosine to inosine was increased in the brains of urease-treated mice and in ammonium-treated cultured astrocytes. This increase in ADAR2 induced RNA editing of 5-HT2B receptors. Cultured astrocytes treated with ammonium lost 5-HT induced Ca2+ signalling and ERK1/2 phosphorylation, indicating dysfunction of 5-HT2B receptors. This is in agreement with our previous observation that edited 5-HT2B receptors no longer respond to 5-HT (Hertz et al., 2014). Ammonium effects are inhibited by ADAR2 siRNA in cultured astrocytes, suggesting that increased gene expression and editing and loss of function of 5-HT2B receptors are results of increased activity of ADAR2. In summary, we have demonstrated that functional malfunction of astrocytic 5-HT2B receptors occurs in animal models of major depression, Parkinson depression and hepatic encephalopathy albeit via different mechanisms. Understanding the role of astrocytic 5-HT2B receptors in different pathological contexts may instigate development of novel therapeutic strategies for treating disease-specific depressive behaviour.
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Abstract
Hepatic encephalopathy (HE) has a major impact on health-related quality of life (HRQOL) in patients, which has clinical and psychosocial consequences. HRQOL in cirrhosis has been measured by generic and liver-specific instruments, with most studies indicating a negative impact of HE. HRQOL abnormalities span daily functioning, sleep–wake cycle changes, and the ability to work. Of these, sleep–wake cycle changes have a major effect on HRQOL, which remains challenging to treat. The personal effect of HRQOL is modulated by the presence of HE, the etiology of cirrhosis, and cognitive reserve. Patients with higher cognitive reserve are able to tolerate HE and its impact on HRQOL better than those with a poor cognitive reserve. The impact of HRQOL impairment is felt by patients (higher mortality and poor daily functioning), as well as by caregivers and families. Caregivers of patients with HE bear a major financial and psychological burden, which may affect their personal health and longevity.
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Affiliation(s)
- Vikki Argent
- Department of Psychological Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Roger Simon Smyth
- Department of Psychological Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
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Lee HH, Chiu CC, Lin JJ, Wang JJ, Lee KT, Sun DP, Shi HY. Impact of preoperative anxiety and depression on quality of life before and after resection of hepatocellular carcinoma. J Affect Disord 2019; 246:361-367. [PMID: 30597297 DOI: 10.1016/j.jad.2018.12.085] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/15/2018] [Accepted: 12/24/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The impact of anxiety and depression symptoms (ADS) is often estimated in terms of clinical endpoints such as the risk of complications and probabilities of readmission and survival. The purpose of this study was to provide a benchmark for capturing the negative effects of ADS on quality of life after hepatocellular carcinoma (HCC) surgery and to provide an evidence base for future research and clinical interventions aimed at understanding and remediating these effects. METHODS This prospective study analyzed 410 HCC patients at three tertiary academic hospitals. The Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Functional Assessment of Cancer Therapy- Hepatobiliary (FACT-H) were administered before HCC surgery and at 6 months, 1 year, and 2 years after HCC surgery. Generalized estimating equations were used to estimate differences-in-differences models for examining the effects of ADS. RESULTS At baseline, 9.0% of the participants had anxiety symptom (BAI > 10), 17.1% had depression symptom (BDI > 13), and 7.1% had ADS. Throughout the study period, anxiety and depression (differences-in-differences value) had significant (P < 0.001) negative net effects on mean scores for all FACT-H dimensions, and the differences gradually increased over time. From baseline through all follow-up years, the two groups significantly (P < 0.001) differed in scores for all FACT-H dimensions, and the differences increased over time. CONCLUSIONS For healthcare providers, this study highlights the need for continued monitoring for ADS in patients who have undergone hepatic resection and the need for timely and appropriate psychological care for these patients.
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Affiliation(s)
- Hao-Hsien Lee
- Department of Surgery, Chi Mei Medical Center, Liouying, Tainan, Taiwan.
| | - Chong-Chi Chiu
- Department of Surgery, Chi Mei Medical Center, Liouying, Tainan, Taiwan; Department of Surgery, Chi Mei Medical Center, Yongkang, Tainan, Taiwan; Department of Electrical Engineering, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - Jin-Jia Lin
- Department of Psychiatry, Chi-Mei Medical Center, Yongkang, Tainan, Taiwan; Department of Psychiatry, Chi-Mei Hospital, Liouying, Tainan, Taiwan; Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jhi-Joung Wang
- Department of Medical Research, Chi Mei Medical Center, Yongkang, Tainan, Taiwan
| | - King-Teh Lee
- Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, 100-Shih-Chun 1st Road, Kaohsiung 80708, Taiwan
| | - Ding-Ping Sun
- Department of Surgery, Chi Mei Medical Center, Yongkang, Tainan, Taiwan
| | - Hon-Yi Shi
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, 100-Shih-Chun 1st Road, Kaohsiung 80708, Taiwan; Department of Business Management, National Sun Yat-sen University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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Malaguarnera M, Llansola M, Balzano T, Gómez-Giménez B, Antúnez-Muñoz C, Martínez-Alarcón N, Mahdinia R, Felipo V. Bicuculline Reduces Neuroinflammation in Hippocampus and Improves Spatial Learning and Anxiety in Hyperammonemic Rats. Role of Glutamate Receptors. Front Pharmacol 2019; 10:132. [PMID: 30858801 PMCID: PMC6397886 DOI: 10.3389/fphar.2019.00132] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 02/05/2019] [Indexed: 01/29/2023] Open
Abstract
Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In hyperammonemia, enhanced activation of GABAA receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABAA receptors with bicuculline.
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Affiliation(s)
- Michele Malaguarnera
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Valencia, Spain
| | - Marta Llansola
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Valencia, Spain
| | - Tiziano Balzano
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Valencia, Spain
| | - Belén Gómez-Giménez
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Valencia, Spain
| | - Carles Antúnez-Muñoz
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Valencia, Spain
| | - Núria Martínez-Alarcón
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Valencia, Spain
| | - Rahebeh Mahdinia
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Valencia, Spain
- Faculty of Biology, Damghan University, Damghan, Iran
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe de Valencia, Valencia, Spain
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45
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Buganza-Torio E, Mitchell N, Abraldes JG, Thomas L, Ma M, Bailey RJ, Tandon P. Depression in cirrhosis - a prospective evaluation of the prevalence, predictors and development of a screening nomogram. Aliment Pharmacol Ther 2019; 49:194-201. [PMID: 30485460 DOI: 10.1111/apt.15068] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 08/09/2018] [Accepted: 10/29/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Depression is associated with substantial morbidity and mortality in cirrhosis, but is underdiagnosed and undertreated. AIMS Using the Mini International Neuropsychiatric Interview (MINI) as a gold-standard, to determine prevalence, predictors, and outcomes of depression, and to develop a screening nomogram for use in cirrhosis patients. METHODS Cirrhotic outpatients 18-80 years of age, not on anti-depressants, were consecutively recruited from liver clinics at three tertiary care hospitals. Baseline health-related quality of life (HRQoL) and frailty were determined by the chronic liver disease questionnaire, EQ-VAS, Clinical Frailty Scale and Fried Frailty Criteria. Depression was identified using the MINI and participants were followed up to 6 months to determine unplanned hospitalization/death. RESULTS Of 305 patients, 62% were male; mean age 55(10) years; mean MELD 12.5(5), 61% Child Pugh B/C. Prevalence of depression 18% by MINI. Patients with depression had lower baseline HRQoL and higher frailty scores. Five independently predictive factors were used to develop a clinical nomogram for the diagnosis of clinical depression. These included three Hospital Anxiety and Depression Screening tool variables: "I have lost interest in my appearance" (adjusted odds ratio [aOR] 2.2, P = 0.006), "I look forward with enjoyment to things" (aOR 2.0, P = 0.02), "I feel cheerful" (aOR 2.8, P = 0.002), and two demographic variables: younger age (aOR 0.92, P = 0.001) and not being married or in a common-law relationship (aOR 0.30, P = 0.008). CONCLUSIONS Depression is common in patients with cirrhosis. It has a significant impact on HRQoL and functional status. The developed clinical nomogram is promising for the rapid screening of depression in patients with cirrhosis.
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Affiliation(s)
- Elizabeth Buganza-Torio
- Department of Medicine, Cirrhosis Care Clinic, University of Alberta, Edmonton, Alberta.,Liver Transplant Unit, University of Alberta, Edmonton, Alberta
| | - Nicholas Mitchell
- Liver Transplant Unit, University of Alberta, Edmonton, Alberta.,Department of Psychiatry, University of Alberta, Edmonton, Alberta
| | - Juan G Abraldes
- Department of Medicine, Cirrhosis Care Clinic, University of Alberta, Edmonton, Alberta.,Liver Transplant Unit, University of Alberta, Edmonton, Alberta
| | - Lesley Thomas
- Department of Medicine, Cirrhosis Care Clinic, University of Alberta, Edmonton, Alberta
| | - Mang Ma
- Department of Medicine, Cirrhosis Care Clinic, University of Alberta, Edmonton, Alberta
| | | | - Puneeta Tandon
- Department of Medicine, Cirrhosis Care Clinic, University of Alberta, Edmonton, Alberta.,Liver Transplant Unit, University of Alberta, Edmonton, Alberta
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46
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Hjorth M, Sjöberg D, Svanberg A, Kaminsky E, Langenskiöld S, Rorsman F. Nurse-led clinic for patients with liver cirrhosis-effects on health-related quality of life: study protocol of a pragmatic multicentre randomised controlled trial. BMJ Open 2018; 8:e023064. [PMID: 30337316 PMCID: PMC6196856 DOI: 10.1136/bmjopen-2018-023064] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Liver cirrhosis affects health-related quality of life (HRQoL) even in its early stages. Morbidity is especially high when the disease decompensates and self-care actions become essential. Nurse involvement in secondary prevention in other chronic diseases has contributed to better symptom control, less need of inpatient care and improved HRQoL. In order to evaluate the impact of nurse involvement in the follow-up of patients with liver cirrhosis, we decided to compare structured nurse-led clinics, inspired by Dorothea Orem's nursing theory and motivational strategies, with a group of patients receiving standard care. The primary outcome is HRQoL and the secondary outcomes are quality of care, visits to outpatient clinics or hospitals, disease progress and health literacy. METHODS AND ANALYSIS This is a pragmatic, multicentre randomised controlled study conducted at six Swedish hepatology departments. Eligible patients are adults with diagnosed cirrhosis of the liver (n=500). Participants are randomised into either an intervention with nurse-led follow-up group or into a standard of care group. Recruitment started in November 2016 and is expected to proceed until 2020. Primary outcomes are physical and mental HRQoL measured by RAND-36 at enrolment, after 1 and 2 years. ETHICS AND DISSEMINATION The study is ethically approved by the Regional Ethical Review Board in Uppsala. The results shall be disseminated in international conferences and peer-reviewed articles. TRIAL REGISTRATION NUMBER NCT02957253; Pre-results.
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Affiliation(s)
- Maria Hjorth
- Center of Clinical Reaerch in Dalarna, Falun, Sweden
- Department of Medical Sciences, Uppsala Universitet Medicinska fakulteten, Uppsala, Sweden
| | | | - Anncarin Svanberg
- Department of Medical Sciences, Uppsala Universitet Medicinska fakulteten, Uppsala, Sweden
- Department of Public Health and Caring Sciences, Uppsala University, Falun, Sweden
- Dalarna University, Falun, Sweden
| | - Elenor Kaminsky
- Department of Public Health and Caring Sciences, Uppsala University, Falun, Sweden
| | - Sophie Langenskiöld
- Department of Public Health and Caring Sciences, Uppsala University, Falun, Sweden
| | - Fredrik Rorsman
- Department of Medical Sciences, Uppsala Universitet Medicinska fakulteten, Uppsala, Sweden
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47
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Lee KT, Lin JJ, Shi HY. Anxiety and depression are associated with long-term outcomes of hepatocellular carcinoma: A nationwide study of a cohort from Taiwan. World J Biol Psychiatry 2018; 19:431-439. [PMID: 28000517 DOI: 10.1080/15622975.2016.1273548] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVES A natural experimental design was coupled with propensity score matching to assess the risks of anxiety and depression and to assess the longitudinal effects of anxiety and depression on healthcare utilisation and mortality in hepatocellular carcinoma (HCC) patients. METHODS This nationwide population-based cohort study retrospectively analysed 7304 patients treated for HCC during 1996-2010. Generalised estimating equations were used to estimate differences-in-differences models for examining the effects of anxiety and depression disorders. RESULTS Independent risk factors for anxiety and depression in the HCC patients were female gender (hazard ratio (HR) 1.45; P < 0.001), Charlson co-morbidity index score (HR 1.12; P = 0.005), and liver cirrhosis (HR 1.35; P = 0.004). Anxiety and depression (differences-in-differences value) had a significant (P < 0.001) positive net effect on number of physician visits. Furthermore, the mean overall survival time was 83.4 months (SD 5.4 months) in the anxiety/depression group and 65.4 months (SD 4.8 months) in the non-disorder group. Additionally, the overall survival rate was significantly higher in the anxiety/depression group compared to the non-disorder group during the study period (P = 0.003). CONCLUSIONS Anxiety disorders and depression disorders are associated with a significantly increased overall survival rate in HCC patients. However, further studies are needed to investigate this association.
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Affiliation(s)
- King-Teh Lee
- a Department of Healthcare Administration and Medical Informatics , Kaohsiung Medical University , Kaohsiung , Taiwan.,b Division of Hepatobiliary Surgery, Department of Surgery , Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
| | - Jin-Jia Lin
- c Department of Psychiatry , Chi-Mei Medical Center , Tainan , Taiwan.,d Department of Psychiatry , Chi-Mei Hospital , Liouying , Tainan , Taiwan.,e Department of Psychiatry, School of Medicine, College of Medicine , Taipei Medical University , Taipei , Taiwan
| | - Hon-Yi Shi
- a Department of Healthcare Administration and Medical Informatics , Kaohsiung Medical University , Kaohsiung , Taiwan
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48
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Mudumbi SK, Bourgeois CE, Hoppman NA, Smith CH, Verma M, Bakitas MA, Brown CJ, Markland AD. Palliative Care and Hospice Interventions in Decompensated Cirrhosis and Hepatocellular Carcinoma: A Rapid Review of Literature. J Palliat Med 2018; 21:1177-1184. [PMID: 29698124 PMCID: PMC6104656 DOI: 10.1089/jpm.2017.0656] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2018] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Patients with decompensated cirrhosis (DC) and/or hepatocellular carcinoma (HCC) have a high symptom burden and mortality and may benefit from palliative care (PC) and hospice interventions. OBJECTIVE Our aim was to search published literature to determine the impact of PC and hospice interventions for patients with DC/HCC. METHODS We searched electronic databases for adults with DC/HCC who received PC, using a rapid review methodology. Data were extracted for study design, participant and intervention characteristics, and three main groups of outcomes: healthcare resource utilization (HRU), end-of-life care (EOLC), and patient-reported outcomes. RESULTS Of 2466 results, eight were included in final results. There were six retrospective cohort studies, one prospective cohort, and one quality improvement study. Five of eight studies had a high risk of bias and seven studied patients with HCC. A majority found a reduction in HRU (total cost of hospitalization, number of emergency department visits, hospital, and critical care admissions). Some studies found an impact on EOLC, including location of death (less likely to die in the hospital) and resuscitation (less likely to have resuscitation). One study evaluated survival and found hospice had no impact and another showed improvement of symptom burden. CONCLUSION Studies included suggest that PC and hospice interventions in patients with DC/HCC reduce HRU, impact EOLC, and improve symptoms. Given the few number of studies, heterogeneity of interventions and outcomes, and high risk of bias, further high-quality research is needed on PC and hospice interventions with a greater focus on DC.
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Affiliation(s)
- Sandhya K. Mudumbi
- Center for Palliative and Supportive Care, University of Alabama at Birmingham, Birmingham, Alabama
- Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- Health Services and Outcomes Research Post-Doctoral Training Program, University of Alabama at Birmingham, Birmingham, Alabama
| | | | - Nicholas A. Hoppman
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Catherine H. Smith
- Lister Hill Library of the Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama
| | - Manisha Verma
- Division of Hepatology, Department of Transplantation, Einstein Healthcare Network, Philadelphia, Pennsylvania
| | - Marie A. Bakitas
- Center for Palliative and Supportive Care, University of Alabama at Birmingham, Birmingham, Alabama
- University of Alabama at Birmingham School of Nursing, Birmingham, Alabama
| | - Cynthia J. Brown
- Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- Department of Veterans Affairs Birmingham/Atlanta Geriatric Research, Education and Clinical Center, Birmingham, Alabama
- Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, Birmingham, Alabama
| | - Alayne D. Markland
- Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- Department of Veterans Affairs Birmingham/Atlanta Geriatric Research, Education and Clinical Center, Birmingham, Alabama
- Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, Birmingham, Alabama
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49
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Langberg KM, Kapo JM, Taddei TH. Palliative care in decompensated cirrhosis: A review. Liver Int 2018; 38:768-775. [PMID: 29112338 DOI: 10.1111/liv.13620] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 10/30/2017] [Indexed: 12/16/2022]
Abstract
Decompensated cirrhosis is an illness that causes tremendous suffering. The incidence of cirrhosis is increasing and rates of liver transplant, the only cure, remain stagnant. Palliative care is focused on improving quality of life for patients with serious illness by addressing advanced care planning, alleviating physical symptoms and providing emotional support to the patient and family. Palliative care is used infrequently in patients with decompensated cirrhosis. The allure of transplant as a potential treatment option for cirrhosis, misperceptions about the role of palliative care and difficulty predicting prognosis in liver disease are potential contributors to the underutilization of palliative care in this patient population. Studies have demonstrated some benefit of palliative care in patients with decompensated cirrhosis but the literature is limited to small observational studies. There is evidence that palliative care consultation in other patient populations lowers hospital costs and ICU utilization and improves symptom control and patient satisfaction. Prospective randomized control trials are needed to investigate the effects of palliative care on traditional- and patient-reported outcomes as well as cost of care in decompensated cirrhosis for transplant eligible and ineligible patient populations.
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Affiliation(s)
- Karl M Langberg
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jennifer M Kapo
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Tamar H Taddei
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.,VA Connecticut Healthcare System, West Haven, CT, USA
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50
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Knaul FM, Farmer PE, Krakauer EL, De Lima L, Bhadelia A, Jiang Kwete X, Arreola-Ornelas H, Gómez-Dantés O, Rodriguez NM, Alleyne GAO, Connor SR, Hunter DJ, Lohman D, Radbruch L, Del Rocío Sáenz Madrigal M, Atun R, Foley KM, Frenk J, Jamison DT, Rajagopal MR. Alleviating the access abyss in palliative care and pain relief-an imperative of universal health coverage: the Lancet Commission report. Lancet 2018; 391:1391-1454. [PMID: 29032993 DOI: 10.1016/s0140-6736(17)32513-8] [Citation(s) in RCA: 735] [Impact Index Per Article: 105.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/28/2017] [Accepted: 07/28/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Felicia Marie Knaul
- Department of Public Health Sciences, Leonard M. Miller School of Medicine, University of Miami, Coral Gables, FL, USA; Institute for Advanced Study of the Americas, University of Miami, Coral Gables, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, FL, USA; Tómatelo a Pecho, A.C., Mexico City, Mexico; Fundación Mexicana para la Salud, A.C., Mexico City, Mexico.
| | | | - Eric L Krakauer
- Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA; World Health Organization, Geneva, Switzerland
| | - Liliana De Lima
- International Association for Hospice and Palliative Care, Houston, TX, USA
| | - Afsan Bhadelia
- Institute for Advanced Study of the Americas, University of Miami, Coral Gables, FL, USA; Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Xiaoxiao Jiang Kwete
- Institute for Advanced Study of the Americas, University of Miami, Coral Gables, FL, USA; Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Héctor Arreola-Ornelas
- Institute for Advanced Study of the Americas, University of Miami, Coral Gables, FL, USA; Tómatelo a Pecho, A.C., Mexico City, Mexico; Fundación Mexicana para la Salud, A.C., Mexico City, Mexico
| | | | - Natalia M Rodriguez
- Institute for Advanced Study of the Americas, University of Miami, Coral Gables, FL, USA
| | - George A O Alleyne
- Pan American Health Organization, Regional Office of WHO, Washington, DC, USA
| | | | - David J Hunter
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Diederik Lohman
- Health and Human Rights Division, Human Rights Watch, Maplewood, NJ, USA
| | - Lukas Radbruch
- International Association for Hospice and Palliative Care, Houston, TX, USA; Department of Palliative Medicine, University Hospital Bonn, Germany; The Malteser Hospital, Bonn, Germany
| | | | - Rifat Atun
- Harvard Medical School, Boston, MA, USA; Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Health Policy and Management, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | | | - Julio Frenk
- Department of Public Health Sciences, Leonard M. Miller School of Medicine, University of Miami, Coral Gables, FL, USA; School of Business Administration, University of Miami, Coral Gables, FL, USA
| | | | - M R Rajagopal
- Trivandrum Institute of Palliative Sciences, WHO Collaborating Centre for Training and Policy on Access to Pain Relief, Pallium India, Kerala, India
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