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Pflugrad H, Hennemann AK. Reversibility of structural and functional alterations of hepatic encephalopathy. Metab Brain Dis 2024; 40:59. [PMID: 39661215 DOI: 10.1007/s11011-024-01497-3] [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: 03/04/2024] [Accepted: 12/09/2024] [Indexed: 12/12/2024]
Abstract
Hepatic Encephalopathy (HE) is a frequent complication of chronic liver disease. Type C HE mainly appears in episodes; only seldom chronic persistent forms occur. HE can lead to hospitalization and it has a huge impact on the health related quality of life. Symptoms of HE comprise alterations of the mental status and HE was associated with structural brain alterations. After the resolution of HE episodes alterations of the mental status seem to be reversible. However, cognitive impairment was described to persist in some patients in between HE episodes questioning the full reversibility of functional and structural alterations of HE. The causative treatment of chronic liver disease and subsequent HE episodes is liver transplantation. After liver transplantation functional and structural alterations caused by HE seem to be reversible, however, neurological complications in the first weeks after liver transplantation are frequent, especially in patients with a history of HE before transplantation. Furthermore, in patients in the long term after liver transplantation cognitive dysfunction was described. The underlying causes discussed are residual HE, side effects of immunosuppressive therapy and cerebrovascular disease besides others. It is an important question for patients and caregivers whether HE is a fully reversible episodic phenomenon or if it leads to persistent structural and functional brain alterations even after liver transplantation.
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Affiliation(s)
- Henning Pflugrad
- Department of Neurology, Agaplesion ev. Klinikum Schaumburg gGmbH, Zum Schaumburger Klinikum 1, Obernkirchen, 31683, Germany.
| | - Ann-Katrin Hennemann
- Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
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Tong XY, Norenberg MD, Paidas MJ, Shamaladevi N, Salgueiro L, Jaszberenyi M, John B, Hussain H, El Hiba O, Abdeljalil EG, Bilal EM, Natarajan S, Romaguera R, Papayan S, Carden AK, Ramamoorthy R, Elumalai N, Schally AV, Nithura J, Patrizio R, Jayakumar AR. Mechanism of Alzheimer type II astrocyte development in hepatic encephalopathy. Neurochem Int 2024; 180:105866. [PMID: 39369794 DOI: 10.1016/j.neuint.2024.105866] [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: 05/14/2024] [Revised: 09/19/2024] [Accepted: 09/22/2024] [Indexed: 10/08/2024]
Abstract
Type C hepatic encephalopathy (Type C HE) is a major and complex neurological condition that occurs following chronic liver failure. The molecular basis of Type C HE remains elusive. Type C HE is characterized by mental confusion, cognitive and motor disturbances. The presence of Alzheimer type II astrocytes (AT2A) is the key histopathological finding observed in Type C HE. However, nothing is currently known regarding AT2A development and its involvement in cognitive, and motor deficits in Type C HE. We, therefore, examined in rats the mechanisms by which liver failure contributes to the progression of AT2A, and its role in the development of cognitive and motor deficits in thioacetamide (TAA) model of Type C HE. We and others earlier reported increased oxidative/nitrosative stress (ONS), JNK1/2, and cMyc activation in ammonia-treated astrocyte cultures, as well as in brains from chronic liver failure. We now found increased levels of astrocytic glia maturation factor (GMF, a factor strongly implicated in neuroinflammation), as well as various inflammatory factors (IL-1β, TNF-α, IL-6, MMP-3, COX2, CXCL1, and PGE2), and reduced levels of GFAP and increased levels of aggregated nuclear protein Lamin A/C in rat brain cortex post-chronic liver failure. We also found increased levels of GMF and inflammatory factors (MMP-3, COX2, CXCL1, and PGE2) in astrocytes post-ammonia treatment in vitro. Additionally, pharmacological inhibition of upstream signaling of GMF (ONS, JNK1/2, and cMyc) or GMF inhibitors W-7 and trifluoperazine significantly reduced the levels of inflammatory factors, the number of AT2A cells, as well as the cognitive and motor deficits in TAA-treated rats. Increased levels of GMF were also identified in human post-mortem brain sections. These findings strongly suggest that increased levels of astrocytic GMF due to elevated levels of ONS, JNK1/2, and cMyc and the subsequent inflammation contribute to the development of AT2A and the consequent cognitive, and motor deficits in chronic liver failure.
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Affiliation(s)
- Xiao Y Tong
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
| | - Michael D Norenberg
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
| | - Michael J Paidas
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA; Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, USA
| | | | - Luis Salgueiro
- General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA
| | - Miklos Jaszberenyi
- General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA; Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary
| | - Binu John
- General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA
| | - Hussain Hussain
- Larkin Community Hospital, Department of Internal Medicine and Infectious Disease, Miami, FL, USA
| | - Omar El Hiba
- Laboratory of Anthropogenic, Biotechnology, and Health, Nutritional Physiopathologies, Neuroscience and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av Des facultés, 24000, El Jadida, Morocco; The Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Health Sciences and Technology, Morocco
| | - El Got Abdeljalil
- Laboratory of Anthropogenic, Biotechnology, and Health, Nutritional Physiopathologies, Neuroscience and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av Des facultés, 24000, El Jadida, Morocco; The Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Health Sciences and Technology, Morocco
| | - El-Mansoury Bilal
- Laboratory of Anthropogenic, Biotechnology, and Health, Nutritional Physiopathologies, Neuroscience and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av Des facultés, 24000, El Jadida, Morocco; The Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Health Sciences and Technology, Morocco
| | - Sampath Natarajan
- Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Tamil Nadu, India
| | - Rita Romaguera
- Pathology and Laboratory Medicine, Department of Veterans Affairs, Miami, FL, 33125, USA
| | - Stanislav Papayan
- Pathology and Laboratory Medicine, Department of Veterans Affairs, Miami, FL, 33125, USA
| | - Arianna K Carden
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Rajalakshmi Ramamoorthy
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Nila Elumalai
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Andrew V Schally
- Endocrine, Polypeptide, and Cancer Institute, Department of Veterans Affairs, Miami, FL, 33125, USA
| | | | - Rebecca Patrizio
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Arumugam R Jayakumar
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA; General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA; Neuropathology Section, Veterans Affairs Medical Center, Miami, FL, USA; R&D Services and South Florida VA Foundation for Research and Education Inc, Veterans Affairs Medical Center, Miami, FL, USA.
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Nasr Azadani H, Nassiri Toosi M, Shahmahmoodi S, Nejati A, Rahimi H, Farahmand M, Keshavarz A, Ghorbani Motlagh F, Samimi-Rad K. New insights into potential biomarkers and their roles in biological processes associated with hepatitis C-related liver cirrhosis by hepatic RNA-seq-based transcriptome profiling. Virus Res 2024; 349:199457. [PMID: 39216827 DOI: 10.1016/j.virusres.2024.199457] [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: 05/07/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Chronic hepatitis C virus infection is a major cause of mortality due to liver cirrhosis globally. Despite the advances in recent therapeutic strategies, there is yet a high burden of HCV-related cirrhosis worldwide concerning low coverage of newly developed antiviral therapies, insufficient validity of the current diagnostic methods for cirrhosis, and incomplete understanding of the pathogenesis in this stage of liver disease. Hence we aimed to clarify the molecular events in HCV-related cirrhosis and identify a liver-specific gene signature to potentially improve diagnosis and prognosis of the disease. Through RNA-seq transcriptome profiling of liver samples of Iranian patients with HCV-related cirrhosis, the differentially expressed genes (DEGs) were identified and subjected to functional annotation including biological process (BP) and molecular function (MF) analysis and also KEGG pathway enrichment analysis. Furthermore, the validation of RNA-seq data was investigated for seven candidate genes using qRT-PCR. Moreover, the diagnostic and prognostic power of validated DEGs were analyzed in both forms of individual DEG and combined biomarkers through receiver operating characteristic (ROC) analysis. Finally, we explored the pair-wise correlation of these six validated DEGs in a new approach. We identified 838 significant DEGs (padj ˂0.05) enriching 375 and 15 significant terms subjected to BP and MF, respectively (false discovery rate ˂ 0.01) and 46 significant pathways (p-value ˂ 0.05). Most of these biological processes and pathways were related to inflammation, immune responses, and cellular processes participating somewhat in the pathogenesis of liver disease. Interestingly, some neurological-associated genes and pathways were involved in HCV cirrhosis-related neuropsychiatric disorders. Out of seven candidate genes, six DEGs, including inflammation-related genes ISLR, LTB, ZAP70, KLRB1, and neuronal-related genes MOXD1 and Slitrk3 were significantly confirmed by qRT-PCR. There was a close agreement in the expression change results between RNA-seq and qRT-PCR for our candidate genes except for SAA2-SAA4 (P= 0.8). High validity and reproducibility of six novel DEGs as diagnostic and prognostic biomarkers were observed. We also found several pair-wise correlations between validated DEGs. Our findings indicate that the six genes LTB, ZAP70, KLRB1, ISLR, MOXD1, and Slitrk3 could stand as promising biomarkers for diagnosing of HCV-related cirrhosis. However, further studies are recommended to validate the diagnostic potential of these biomarkers and evaluate their capability as targets for the prevention and treatment of cirrhosis disease.
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Affiliation(s)
- Hossein Nasr Azadani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohssen Nassiri Toosi
- Liver Transplantation Research Center, Imam-Khomeini Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Shohreh Shahmahmoodi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Food Microbiology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Nejati
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamzeh Rahimi
- Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mohammad Farahmand
- Pediatric Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Keshavarz
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ghorbani Motlagh
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Katayoun Samimi-Rad
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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Lin S, Qi R, Lin X, Chen S, Zhang L, Qiu Y. Association Between MRI-Assessed Patterns of Connectome Gradient and Gene-Expression Profiles in Two Independent Patient Cohorts With Hepatitis B Virus-Related Cirrhosis. J Magn Reson Imaging 2023; 58:1863-1874. [PMID: 37022091 DOI: 10.1002/jmri.28732] [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: 01/09/2023] [Revised: 03/27/2023] [Accepted: 03/28/2023] [Indexed: 04/07/2023] Open
Abstract
BACKGROUND Patients with hepatitis B virus-related cirrhosis (HBV-RC) exhibit progressive neurologic dysfunction from primary sensorimotor to high-order cognition, as their disease advances. However, the exact neurobiologic mechanisms and the potential association with gene-expression profiles are not fully understood. PURPOSE To explore the hierarchical disorganization in the large-scale functional connectomes in HBV-RC patients and to investigate its potential underlying molecular basis. STUDY TYPE Prospective. POPULATION Fifty HBV-RC patients and 40 controls (Cohort 1) and 30 HBV-RC patients and 38 controls (Cohort 2). FIELD STRENGTH/SEQUENCE Gradient-echo echo-planar and fast field echo sequences at 3.0 T (Cohort 1) and 1.5 T (Cohort 2). ASSESSMENT Data were processed with Dpabi and the BrainSpace package. Gradient scores were evaluated from global to voxel level. Cognitive measurement and patients grouping were based on psychometric hepatic encephalopathy scores. The whole-brain microarray-based gene-expression data were obtained from the AIBS website. STATISTICAL TESTS One-way ANOVA, chi-square test, two-sample t-test, Kruskal-Wallis test, Spearman's correlation coefficient (r), the gaussian random field correction, false discovery rate (FDR) correction and the Bonferroni correction. Significance level: P < 0.05. RESULTS HBV-RC patients exhibited a robust and replicable connectome gradient dysfunction, which was significantly associated with the gene-expression profiles in both cohorts (r = 0.52 and r = 0.56, respectively). The most correlated genes were enriched in γ-aminobutyric acid (GABA) and GABA-related receptor genes (FDR q value <0.05). Moreover, the connectome gradient dysfunction at network level observed in HBV-RC patients correlated with their poor cognitive performance (Cohort 2: visual network, r = -0.56; subcortical network, r = 0.66; frontoparietal network, r = 0.51). DATA CONCLUSION HBV-RC patients had hierarchical disorganization in the large-scale functional connectomes, which may underly their cognitive impairment. In addition, we showed the potential molecular mechanism of the connectome gradient dysfunction, which suggested the importance of GABA and GABA-related receptor genes. EVIDENCE LEVEL 2 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Shiwei Lin
- Department of Radiology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Rongfeng Qi
- Department of Radiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaoshan Lin
- Department of Radiology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Shengli Chen
- Department of Radiology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Longjiang Zhang
- Department of Radiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yingwei Qiu
- Department of Radiology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, China
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Diesing TS. Neurologic Manifestations of Gastrointestinal and Nutritional Disorders. Continuum (Minneap Minn) 2023; 29:708-733. [PMID: 37341328 DOI: 10.1212/con.0000000000001235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/22/2023]
Abstract
OBJECTIVE A tie between nutritional or gastrointestinal and neurologic disease has been recognized for centuries. Many gastrointestinal disorders are associated with neurologic disease through nutritional, immune-mediated, or degenerative pathophysiologies. This article reviews neurologic disorders in patients with gastrointestinal disease and gastrointestinal manifestations in their own neurologic patients. LATEST DEVELOPMENTS Development of new gastric and bariatric surgical procedures and the widespread use of over-the-counter gastric acid-reducing medications continue to create vitamin and nutritional deficiencies despite modern diet and supplementation. Some supplements, such as vitamin A, vitamin B6, and selenium, themselves are now found to cause disease. Recent work has shown extraintestinal and neurologic manifestations of inflammatory bowel disease. Chronic brain damage in liver disease has been recognized, and the opportunity to intervene may exist in the covert beginning stages. The characterization of gluten-related neurologic symptoms and differentiation from those of celiac disease is an evolving body of work. ESSENTIAL POINTS Gastrointestinal and neurologic diseases related to common immune-mediated, degenerative, or infectious mechanisms are common and can coexist in the same patient. Furthermore, gastrointestinal disease may cause neurologic complications because of nutritional inadequacies, malabsorption, and hepatic dysfunction. In many cases, the complications are treatable but have subtle or protean presentations. Therefore, the consulting neurologist must be current in knowledge of the growing ties between gastrointestinal and neurologic disease.
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The Management of Postoperative Cognitive Dysfunction in Cirrhotic Patients: An Overview of the Literature. Medicina (B Aires) 2023; 59:medicina59030465. [PMID: 36984466 PMCID: PMC10053389 DOI: 10.3390/medicina59030465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/03/2023] Open
Abstract
Background and objectives: Postoperative cognitive dysfunction (POCD) represents a decreased cognitive performance in patients undergoing general anesthesia for major surgery. Since liver cirrhosis is associated with high mortality and morbidity rates, cirrhotic patients also assemble many risk factors for POCD. Therefore, preserving cognition after major surgery is a priority, especially in this group of patients. The purpose of this review is to summarize the current knowledge regarding the effectiveness of perioperative therapeutic strategies in terms of cognitive dysfunction reduction. Data Collection: Using medical search engines such as PubMed, Google Scholar, and Cochrane library, we analyzed articles on topics such as: POCD, perioperative management in patients with cirrhosis, hepatic encephalopathy, general anesthesia in patients with liver cirrhosis, depth of anesthesia, virtual reality in perioperative settings. We included 115 relevant original articles, reviews and meta-analyses, and other article types such as case reports, guidelines, editorials, and medical books. Results: According to the reviewed literature, the predictive capacity of the common clinical tools used to quantify cognitive dysfunction in cirrhotic settings is reduced in perioperative settings; however, novel neuropsychological tools could manage to better identify the subclinical forms of perioperative cognitive impairments in cirrhotic patients. Moreover, patients with preoperative hepatic encephalopathy could benefit from specific preventive strategies aimed to reduce the risk of further neurocognitive deterioration. Intraoperatively, the adequate monitoring of the anesthesia depth, appropriate anesthetics use, and an opioid-sparing technique have shown favorable results in terms of POCD. Early recovery after surgery (ERAS) protocols should be implemented in the postoperative setting. Other pharmacological strategies provided conflicting results in reducing POCD in cirrhotic patients. Conclusions: The perioperative management of the cognitive function of cirrhotic patients is challenging for anesthesia providers, with specific and targeted therapies for POCD still sparse. Therefore, the implementation of preventive strategies appears to remain the optimal attitude. Further research is needed for a better understanding of POCD, especially in cirrhotic patients.
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A dynamic nomogram to predict transplant-free mortality in patients with hepatitis B-related cirrhosis and overt hepatic encephalopathy. Int Immunopharmacol 2022; 108:108879. [PMID: 35623289 DOI: 10.1016/j.intimp.2022.108879] [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: 12/25/2021] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Overt hepatic encephalopathy (OHE) is a serious complication of liver disease. We aimed to develop a dynamic nomogram for estimating the probability of 30-day transplant-free mortality in patients with OHE and hepatitis B-related cirrhosis (HBC). METHODS We identified 402 patients with OHE and HBC at the Beijing Ditan Hospital between January 2011 and July 2016. Independent risk factors were determined using multivariate Cox proportional hazards regression analysis. A dynamic nomogram was established to predict the probability of 30-day transplant-free mortality. The discrimination and clinical usefulness of the nomogram were estimated using the area under the receiver operating characteristic (AUC) and calibration curves, and decision curve analysis. A prospective cohort of 208 patients was enrolled for validation. RESULTS The model for end-stage liver disease (MELD) score and neutrophil-to-lymphocyte ratio (NLR) were independently associated with the 30-day transplant-free mortality. The AUC values of the nomogram were 0.881 and 0.879 in the derivation and validation cohorts, respectively, and the discrimination ability was superior to that of the established models. The calibration plot fitted the predicted survival and observed probabilities well. The incidence of mortality was 2.0% (3/151) in patients with MELD scores < 23 and NLR < 4, and 55.4% (41/92) in those with MELD scores ≥ 23 and NLR ≥ 4. CONCLUSIONS The dynamic nomogram can predict the risk of 30-day transplant-free mortality in patients with OHE and HBC. Patients with MELD scores ≥ 23 and NLR ≥ 4 have a high mortality rate and should be admitted to intensive care.
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Zhu L, Zhang W, Chen L, Ren Y, Cao Y, Sun T, Sun B, Liu J, Wang J, Zheng C. Brain Gray Matter Alterations in Hepatic Encephalopathy: A Voxel-Based Meta-Analysis of Whole-Brain Studies. Front Hum Neurosci 2022; 16:838666. [PMID: 35517986 PMCID: PMC9062230 DOI: 10.3389/fnhum.2022.838666] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 02/28/2022] [Indexed: 12/03/2022] Open
Abstract
Background Previous studies on voxel-based morphometry (VBM) have found that there were gray matter alterations in patients with hepatic encephalopathy (HE). However, the reported results were inconsistent and lack a quantitative review. Therefore, this study aims for a quantitative meta-analysis of VBM analysis on patients with HE. Methods The studies in our meta-analysis were collected from Pubmed, Web of Science, and Embase, which were published from January 1947 to October 2021. The seed-based d mapping (SDM) method was applied to quantitatively estimate the regional gray matter abnormalities in patients with HE. A meta-regression analysis was applied to evaluate the relationship between plasma ammonia and gray matter alteration. Results There were nine studies, with sixteen datasets consisting of 333 participants with HE and 429 healthy controls. The pooled and subgroup meta-analyses showed an increase in gray matter volume (GMV) in the bilateral thalamus and the calcarine fissure but a decrease in the GMV in the bilateral insula, the basal ganglia, the anterior cingulate gyrus, and the cerebellum. The meta-regression showed that plasma ammonia was positively associated with the GMV in the left thalamus but was negatively associated with the GMV in the cerebellum and the bilateral striatum. Conclusion Gray matter volume in patients with HE largely varied and could be affected by plasma ammonia. The findings of this study could help us to better understand the pathophysiology of cognitive dysfunction in patients with HE.
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Affiliation(s)
- Licheng Zhu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weihua Zhang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanqiao Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanyan Cao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Sun
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Sun
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Jing Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
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Hansen MKG, Kjærgaard K, Eriksen LL, Grønkjær LL, Mikkelsen ACD, Sandahl TD, Vilstrup H, Thomsen KL, Lauridsen MME. Psychometric methods for diagnosing and monitoring minimal hepatic encephalopathy -current validation level and practical use. Metab Brain Dis 2022; 37:589-605. [PMID: 35102491 DOI: 10.1007/s11011-022-00913-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 01/14/2022] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is cerebral dysfunction caused by liver failure and inflicts 30-40% of patients with liver cirrhosis during their disease course. Clinically manifest HE is often preceded by minimal HE (MHE) - a clinically undetectable cognitive disturbance closely associated with loss of quality of life. Accordingly, detecting and treating MHE improve the patients' daily functioning and prevent HE-related hospital admissions. The scope of this review article is to create an overview of the validation level and usage of psychometric tests used to detect MHE: Portosystemic hepatic encephalopathy test, continuous reaction time test, Stroop EncephalApp, animal naming test, critical flicker frequency test, and inhibitory control test. Our work is aimed at the clinician or scientist who is about to decide on which psychometric test would fit best in their clinic, cohort, or study. First, we outline psychometric test validation obstacles and requirements. Then, we systematically approach the literature on each test and select well-conducted studies to answer the following questions:• Which percentage of patients with cirrhosis does the test deem as having MHE?• Is the test able to predict clinically manifest HE?• Is there a well-known test-retest variation and inter-observer variation?• Is the test able to detect a treatment response?• Is the test result affected by age, educational level, gender, or comorbidities?
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Affiliation(s)
- Mads Kingo Guldberg Hansen
- Department of Gastroenterology and Hepatology, University Hospital South Denmark, Finsensgade 35, 6700, Esbjerg, Denmark.
| | - Kristoffer Kjærgaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Lotte Lindgreen Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Lea Ladegaard Grønkjær
- Department of Gastroenterology and Hepatology, University Hospital South Denmark, Finsensgade 35, 6700, Esbjerg, Denmark
| | - Anne Catrine Daugaard Mikkelsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Thomas Damgaard Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Mette Munk Enok Lauridsen
- Department of Gastroenterology and Hepatology, University Hospital South Denmark, Finsensgade 35, 6700, Esbjerg, Denmark
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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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11
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Li Y, Liu H, Chen K, Wu X, Wu J, Yang Z, Yao L, Wen G, Zhang C, Chen X, Chen X, Tang D, Wang X, Liu J. Pathological Significance and Prognostic Roles of Indirect Bilirubin/Albumin Ratio in Hepatic Encephalopathy. Front Med (Lausanne) 2021; 8:706407. [PMID: 34527681 PMCID: PMC8435674 DOI: 10.3389/fmed.2021.706407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/10/2021] [Indexed: 11/27/2022] Open
Abstract
Background and Aim: Hepatic encephalopathy (HE) is a neurological disease caused by severe liver disease. Early identification of the risk factor is beneficial to the prevention and treatment of HE. Free bilirubin has always been considered to be the culprit of neonatal kernicterus, but there is no research to explore its role in HE. In this study, we aim to study the clinical significance of the indirect bilirubin-albumin ratio in HE. Methods: A retrospective case-control study of 204 patients with liver failure was conducted. Human serum albumin (HSA) or heme oxygenase-1 (HO-1) inhibitor SnPP (Tin protoporphyrin IX dichloride) was injected intraperitoneally into Ugt1−/− mice to establish a treatment model for endogenous hyperbilirubinemia. Results: IBil/albumin ratio (OR = 1.626, 95% CI1.323–2.000, P < 0.001), white blood cell (WBC) (OR = 1.128, 95% CI 1.009–1.262, P = 0.035), ammonia (OR = 1.010, 95% CI 1.001–1.019, P = 0.027), platelet (OR=1.008, 95% CI 1.001–1.016, P = 0.022), Hb (OR = 0.977, 95% CI 0.961–0.994, P = 0.007), and PTA (OR = 0.960, 95% CI 0.933–0.987, P = 0.005) were independent factors of HE. Patients with a history of liver cirrhosis and severe HE (OR = 12.323, 95% CI 3.278–47.076, P < 0.001) were more likely to die during hospitalization. HSA or SnPP treatment improved cerebellum development and reduced apoptosis of cerebellum cells. Conclusion: The IBil/albumin ratio constitutes the most powerful risk factor in the occurrence of HE, and reducing free bilirubin may be a new strategy for HE treatment.
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Affiliation(s)
- Yanling Li
- The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Huiyuan Liu
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Keng Chen
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xueheng Wu
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jiawen Wu
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Zhenjun Yang
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Leyi Yao
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.,Institute of Digestive Disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Guanmei Wen
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Change Zhang
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xin Chen
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xiaohui Chen
- The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
| | - Xuejun Wang
- Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, SD, United States
| | - Jinbao Liu
- Guangzhou Municipal and Guangdong Provincial Key Lab of Protein Modification and Degradation Lab, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.,Institute of Digestive Disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
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12
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Cheng Y, Shen W, Xu J, Amey RC, Huang LX, Zhang XD, Li JL, Akhavan C, Duffy BA, Simon JP, Jiang W, Liu M, Kim H. Neuromarkers from Whole-Brain Functional Connectivity Reveal the Cognitive Recovery Scheme for Overt Hepatic Encephalopathy after Liver Transplantation. eNeuro 2021; 8:ENEURO.0114-21.2021. [PMID: 34376523 PMCID: PMC8376297 DOI: 10.1523/eneuro.0114-21.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/20/2021] [Accepted: 07/26/2021] [Indexed: 11/21/2022] Open
Abstract
Neurocognitive impairment is present in cirrhosis and may be more severe in cirrhosis with overt hepatic encephalopathy (OHE). Liver transplantation (LT) can restore liver function, but how it reverses the impaired brain function is still unclear. MRI of resting-state functional connectivity can help reveal the underlying mechanisms that lead to these cognitive deficits and cognitive recovery. In this study, 64 patients with cirrhosis (28 with OHE; 36 without OHE) and 32 healthy control subjects were recruited for resting-state fMRI. The patients were scanned before and after LT. We evaluated presurgical and postsurgical neurocognitive performance in cirrhosis patients using psychomotor tests. Network-based statistics found significant disrupted connectivity in both groups of cirrhotic patients, with OHE and without OHE, compared with control subjects. However, the presurgical connectivity disruption in patients with OHE affected a greater number of connections than those without OHE. The decrease in functional connectivity for both OHE and non-OHE patient groups was reversed after LT to the level of control subjects. An additional hyperconnected network (i.e., higher connected than control subjects) was observed in OHE patients after LT. Regarding the neural-behavior relationship, the functional network that predicted cognitive performance in healthy individuals showed no correlation in presurgical cirrhotic patients. The impaired neural-behavior relationship was re-established after LT for non-OHE patients, but not for OHE patients. OHE patients displayed abnormal hyperconnectivity and a persistently impaired neural-behavior relationship after LT. Our results suggest that patients with OHE may undergo a different trajectory of postsurgical neurofunctional recovery compared with those without, which needs further clarification in future studies.
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Affiliation(s)
- Yue Cheng
- Department of Radiology, Tianjin First Center Hospital, Tianjin 300192, People's Republic of China
| | - Wen Shen
- Department of Radiology, Tianjin First Center Hospital, Tianjin 300192, People's Republic of China
| | - Junhai Xu
- Tianjin Key Laboratory of Cognitive Computing and Application, School of Artificial Intelligence, College of Intelligence and Computing, Tianjin University, Tianjin 300350, People's Republic of China
| | - Rachel C Amey
- U.S. Army Research Institute for the Behavioral and Social Sciences, Fort Belvoir, Virginia 22060-5610
| | - Li-Xiang Huang
- Department of Radiology, Tianjin First Center Hospital, Tianjin 300192, People's Republic of China
| | - Xiao-Dong Zhang
- Department of Radiology, Tianjin First Center Hospital, Tianjin 300192, People's Republic of China
| | - Jing-Li Li
- Department of Radiology, Tianjin First Center Hospital, Tianjin 300192, People's Republic of China
| | - Cameron Akhavan
- USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, California 90033
| | - Ben A Duffy
- USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, California 90033
| | - Julia Pia Simon
- USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, California 90033
| | - Wenjuan Jiang
- College of Pharmacy, Western University of Health Sciences, Pomona, California 91766-1854
| | - Mengting Liu
- USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, California 90033
| | - Hosung Kim
- USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, California 90033
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13
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Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver Cirrhosis. Am J Gastroenterol 2021; 116:1238-1247. [PMID: 33852451 DOI: 10.14309/ajg.0000000000001164] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION We aimed to define the impact of the genetic background on overt hepatic encephalopathy (HE) in patients with liver cirrhosis by developing a combined clinical-genetic risk score. METHODS Patients suffering from liver cirrhosis from the outpatient clinics of 4 hospitals (n = 600) were included and followed up for at least 5 years until HE bouts, liver transplant, or death. Patients were genotyped for 60 candidate single nucleotide polymorphisms together with the microsatellite in the promoter region of the gene GLS. RESULTS Single nucleotide polymorphisms rs601338 (FUT2), rs5743836 (TRL9), rs2562582 (SLC1A3), rs313853 (SLC1A5), and GLS microsatellite did predict independently the incidence and severity of overt HE and were included as genetic score. Competing risk analysis revealed that bilirubin (subhazard ratio [sHR] 1.30 [1.15-1.48], P < 0.001), albumin (sHR 0.90 [0.86-0.93], P < 0.001), genetic score (sHR 1.90 [1.57-2.30], P < 0.001), and previous episodes of overt HE (sHR 2.60 [1.57-4.29], P < 0.001) were independently associated to HE bouts during the follow-up with an internal (C-index 0.83) and external validation (C-index 0.74). Patients in the low-risk group had 5% and 12% risk of HE at 1 (log-rank 92.1; P < 0.001) and 5 (log-rank 124.1; P < 0.001) years, respectively, whereas 36% and 48% in the high-risk group. DISCUSSION The genetic background influenced overt HE risk and severity. The clinical-genetic HE Risk score, which combined genetic background together with albumin, bilirubin, and previous episodes of overt HE, could be a useful tool to predict overt HE in patients with cirrhosis.
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14
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López-Franco Ó, Morin JP, Cortés-Sol A, Molina-Jiménez T, Del Moral DI, Flores-Muñoz M, Roldán-Roldán G, Juárez-Portilla C, Zepeda RC. Cognitive Impairment After Resolution of Hepatic Encephalopathy: A Systematic Review and Meta-Analysis. Front Neurosci 2021; 15:579263. [PMID: 33790729 PMCID: PMC8006450 DOI: 10.3389/fnins.2021.579263] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 01/14/2021] [Indexed: 12/26/2022] Open
Abstract
Hepatic encephalopathy (HE) is one of the most disabling metabolic diseases. It consists of a complication of liver disease through the action of neurotoxins, such as excessive production of ammonia from liver, resulting in impaired brain function. Its prevalence and incidence are not well known, although it has been established that up to 40% of cirrhotic patients may develop HE. Patients with HE episodes display a wide range of neurological disturbances, from subclinical alterations to coma. Recent evidence suggests that the resolution of hepatic encephalopathy does not fully restore cognitive functioning in cirrhotic patients. Therefore, the aim of this review was to evaluate the evidence supporting the presence of lingering cognitive deficits in patients with a history of HE compared to patients without HE history and how liver transplant affects such outcome in these patients. We performed two distinct meta-analysis of continuous outcomes. In both cases the results were pooled using random-effects models. Our results indicate that cirrhotic patients with a history of HE show clear cognitive deficits compared to control cirrhotic patients (Std. Mean Difference (in SDs) = −0.72 [CI 95%: −0.94, −0.50]) and that these differences are not fully restored after liver transplant (Std. Mean Difference (in SDs) = −0.48 [CI 95%: −0.77, −0.19]).
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Affiliation(s)
- Óscar López-Franco
- Laboratorio de Medicina Traslacional, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | - Jean-Pascal Morin
- Laboratorio de Neurobiología de la Conducta, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico, Mexico
| | | | - Tania Molina-Jiménez
- Instituto Interdisciplinario de Investigaciones de la Universidad de Xalapa, Xalapa, Mexico
| | - Diana I Del Moral
- Programa de Doctorado en Ciencias Biomédicas, Universidad Veracruzana, Xalapa, Mexico
| | - Mónica Flores-Muñoz
- Laboratorio de Medicina Traslacional, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | - Gabriel Roldán-Roldán
- Laboratorio de Neurobiología de la Conducta, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico, Mexico
| | - Claudia Juárez-Portilla
- Laboratorio de Biomedicina Integral y Salud, Centro de Investigaciones Biomédicas, Universidad Veracruzana, Xalapa, Mexico
| | - Rossana C Zepeda
- Laboratorio de Biomedicina Integral y Salud, Centro de Investigaciones Biomédicas, Universidad Veracruzana, Xalapa, Mexico
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15
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Hayward KL, Weersink RA. Improving Medication-Related Outcomes in Chronic Liver Disease. Hepatol Commun 2020; 4:1562-1577. [PMID: 33163829 PMCID: PMC7603526 DOI: 10.1002/hep4.1612] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/20/2020] [Accepted: 09/08/2020] [Indexed: 12/17/2022] Open
Abstract
Patients with chronic liver disease (CLD) are becoming increasingly complex due to the rising prevalence of multimorbidity and polypharmacy. Medications are often essential to manage the underlying liver disease, complications of cirrhosis and portal hypertension, and comorbidities. However, medication-related problems (MRPs) have been associated with adverse patient outcomes, including hospitalization and mortality. Factors that can contribute to MRPs in people with CLD are variable and often entwined. This narrative literature review discusses key barriers and opportunities to modify risk factors and improve medication-related outcomes for people with CLD.
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Affiliation(s)
- Kelly L Hayward
- Centre for Liver Disease Research, Faculty of Medicine The University of Queensland, Translational Research Institute Brisbane QLD Australia.,Department of Gastroenterology and Hepatology Princess Alexandra Hospital Brisbane QLD Australia
| | - Rianne A Weersink
- Department of Clinical Pharmacy Deventer Hospital Deventer The Netherlands
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16
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Bobermin LD, Roppa RHA, Gonçalves CA, Quincozes-Santos A. Ammonia-Induced Glial-Inflammaging. Mol Neurobiol 2020; 57:3552-3567. [DOI: 10.1007/s12035-020-01985-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/08/2020] [Indexed: 12/13/2022]
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17
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Abstract
Hepatic encephalopathy is a major neuropsychiatric complication of liver disease that affects 30% to 40% of cirrhotic patients. Hepatic encephalopathy is characterized by a brain dysfunction that is associated with neurologic complications. Those complications are associated with cognitive impairments, which negatively impacts patients' physical and mental health. In turn, hepatic encephalopathy poses a substantial economic and use burdens to the health care system. This article reviews the multidimensional aspects of the health care burden posed by hepatic encephalopathy.
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18
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Abstract
Hepatic encephalopathy (HE) is a complex condition with multiple causes each with varying degrees of severity. HE negatively impacts patients' quality of life, and it is associated with significant burdens to patients and their caregivers. The prevalence of cirrhosis, the most common risk factor for HE, has steadily increased during recent years. In turn, an upsurge in the clinical and health care burdens related to HE is expected in the upcoming years. This article provides a comprehensive review of the epidemiology of HE.
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Affiliation(s)
- Mohamed I Elsaid
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, Medical Education Building, 1 Robert Wood Johnson, Room 479, New Brunswick, NJ 08903, USA.
| | - Vinod K Rustgi
- Center for Liver Diseases and Liver Masses, Robert Wood Johnson School of Medicine, MedEd Building, Room 466, 1 Robert Wood Johnson Place, New Brunswick, NJ 08901, USA
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19
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Abstract
Hepatic encephalopathy (HE) is one of the major clinical decompensations of cirrhosis, with a high impact on health care resource utilization and cost. For an effective and comprehensive management of HE, the clinicians need to understand the pathophysiologic mechanisms of HE. This review describes the multiorgan processes involved in HE and how several HE precipitants and treatment strategies act on ammonia production, excretion, and neurotoxicity, including the impact of diabetes and use of cannabinoids. The authors also discuss the current and future role of gut microbiome, systemic/central inflammation, and various neurotransmitters for the pathogenesis and treatment of HE.
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Affiliation(s)
- Ariel Jaffe
- Section of Digestive Diseases, Yale Liver Center, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520-8019, USA
| | - Joseph K Lim
- Section of Digestive Diseases, Yale Liver Center, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520-8019, USA; VA Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Sofia Simona Jakab
- Section of Digestive Diseases, Yale Liver Center, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520-8019, USA; VA Connecticut Healthcare System, West Haven, Connecticut, USA.
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20
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Chen HJ, Chen QF, Yang ZT, Shi HB. Aberrant topological organization of the functional brain network associated with prior overt hepatic encephalopathy in cirrhotic patients. Brain Imaging Behav 2019; 13:771-780. [PMID: 29846883 DOI: 10.1007/s11682-018-9896-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A higher risk of cognitive impairments has been found after an overt hepatic encephalopathy (OHE) episode in cirrhotic patients. We investigated the effect of prior OHE episodes on the topological organization of the functional brain network and its association with the relevant cognitive impairments. Resting-state functional MRI data were acquired from 41 cirrhotic patients (19 with prior OHE (Prior-OHE) and 22 without (Non-Prior-OHE)) and 21 healthy controls (HC). A Psychometric Hepatic Encephalopathy Score (PHES) assessed cognition. The whole-brain functional network was constructed by thresholding functional correlation matrices of 90 brain regions (derived from the Automated Anatomic Labeling atlas). The topological properties of the brain network, including small-worldness, network efficiency, and nodal efficiency, were examined using graph theory-based analysis. Globally, the Prior-OHE group had a significantly decreased clustering coefficient and local efficiency, compared with the controls. Locally, the nodal efficiency in the bilateral medial superior frontal gyrus and the right postcentral gyrus decreased in the Prior-OHE group, while the nodal efficiency in the bilateral anterior cingulate/paracingulate gyri and right superior parietal gyrus increased in the Prior-OHE group. The alterations of global and regional network parameters progressed from Non-Prior-OHE to Prior-OHE and the clustering coefficient and local efficiency values were significantly correlated with PHES results. In conclusion, cirrhosis leads to the reduction of brain functional network efficiency, which could be aggravated by a prior OHE episode. Aberrant topological organization of the functional brain network may contribute to a higher risk of cognitive impairments in Prior-OHE patients.
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Affiliation(s)
- Hua-Jun Chen
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
| | - Qiu-Feng Chen
- College of Computer and Information Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Zhe-Ting Yang
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Hai-Bin Shi
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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21
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Young People With Biliary Atresia Requiring Liver Transplantation: A Distinct Population Requiring Specialist Care. Transplantation 2019; 103:e99-e107. [PMID: 30461724 DOI: 10.1097/tp.0000000000002553] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Young people (YP) born with biliary atresia (BA) are an emerging population for adult hepatologists with 40% to 45% of children entering adolescence with their native liver intact. For those requiring liver transplantation (LT) during adolescence, disparity on the waiting list and post-LT outcome for young adults compared with younger and older age groups has stimulated discussion about the optimal timing of listing. In this study, we review our experience of YP with BA requiring LT during adolescence and young adulthood. METHODS Retrospective, single-center review of patients with BA requiring LT > 11 years. RESULTS Thirty-six YP (16 male) underwent LT between 1991 and 2014 at a median age of 16.6 (interquartile range [IQR], 14.2 to 19.5) years. The commonest indications for listing were refractory cholangitis (31%), synthetic failure (25%), and variceal bleeding (14%). Patients listed by the adult team (n = 14) waited longer than those listed by the pediatric team (10 [IQR, 7.7 to 24.6] vs 5.8 [IQR, 4.0 to 15.1] months; P < 0.05) and were more likely to require intensive care support at time of listing (29% vs 5%; P < 0.05). Admission to intensive care unit at listing was associated with poorer patient and graft survival and support from a multidisciplinary liver transition service improved survival. Liver disease severity scores did not correlate with time on waiting list or outcome. CONCLUSIONS YP with BA requires close monitoring by specialists familiar with their condition and timing for LT needs to be fine-tuned to avoid clinical decompensation and improve long-term outcomes.
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22
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Zarantonello L, Turco M, Formentin C, Izquierdo-Altarejos P, Vuerich A, Barcenas Jimenez MJ, Montoliu C, Felipo V, Angeli P, Amodio P, Montagnese S. The influence of HE history, HE status and neuropsychological test type on learning ability in patients with cirrhosis. Liver Int 2019; 39:861-870. [PMID: 30658006 DOI: 10.1111/liv.14046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/06/2018] [Accepted: 01/11/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Learning ability may be impaired in patients with a history of overt hepatic encephalopathy (OHE). The aim of this study was to compare performance on the first/second attempt at a series of tests. METHODS Two hundred and fourteen patients with cirrhosis were enrolled. On the day of study, 41% were classed as unimpaired, 38% as having minimal HE and 21% as having mild OHE; 58% had a history of OHE. Performance was compared between two versions of the trail-making test A (TMT-A), and between the first/second half of a simple/choice reaction time (sRT and cRT), and a working memory test (ScanRT). RESULTS Both patients with and without OHE history improved in TMT-A, sRT and ScanRT. Only patients with no OHE history improved in cRT. All patients, regardless of their HE status on the day of study, improved in TMT-A and sRT. Only patients with mild OHE on the day of study improved in cRT. Only unimpaired patients improved in ScanRT. When OHE history and HE status on the day of study were tested together, only HE status had an effect. The same held true when age, the Model for End Stage Liver Disease (MELD) and educational attainment were adjusted for. CONCLUSIONS HE status on the day of study and the type of neuropsychological test had an effect on learning ability in a well-characterized group of patients with cirrhosis.
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Affiliation(s)
| | - Matteo Turco
- Department of Medicine, University of Padova, Padova, Italy
| | | | - Paula Izquierdo-Altarejos
- Department of Medicine, University of Padova, Padova, Italy.,Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Anna Vuerich
- Department of Medicine, University of Padova, Padova, Italy
| | | | - Carmina Montoliu
- Fundación Investigación Hospital Clínico, Instituto Investigación Sanitaria-INCLIVA, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Paolo Angeli
- Department of Medicine, University of Padova, Padova, Italy
| | - Piero Amodio
- Department of Medicine, University of Padova, Padova, Italy
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Kornerup LS, Pflugrad H, Weissenborn K, Vilstrup H, Dam G. Cognitive impairment after liver transplantation: residual hepatic encephalopathy or posttransplant encephalopathy? Hepat Med 2019; 11:41-46. [PMID: 31040728 PMCID: PMC6456244 DOI: 10.2147/hmer.s144667] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/25/2019] [Indexed: 12/22/2022] Open
Abstract
Liver transplantation (LT) represents the definitive treatment for end-stage liver disease. Cognitive impairment following LT is frequent, referred to as postliver transplant encephalopathy (PLTE). LT removes the underlying chronic liver disease, and until recently hepatic encephalopathy (HE) was assumed to be fully reversible after LT. However, increasing evidence indicates that some degree of cognitive impairment may be present after LT. To which extent PLTE reflects cognitive impairment caused by residual HE (RHE) or the combined effect of other factors affecting brain function before, during, and after LT is not clarified. None of the available psychometric and neurophysiological tests used for detecting HE is shown to be able to distinguish between etiologies. The available, mostly retrospective, clinical studies indicate a high prevalence of abnormal psychometric tests after LT, and not all seem to recover completely. The patients with earlier HE show the most marked improvements, suggesting that the clinical picture of the early PLTE, in fact, represents RHE. Other early post-LT etiologies for PLTE comprise cerebral ischemia, critical illness encephalopathy, and immunosuppressive therapy. Late-onset etiologies comprise diabetes and hypertension, among others. PLTE regardless of etiology is a worrying issue and needs more attention in the form of mechanistic research, development of diagnostic/discriminative tools, and standardized prospective clinical studies.
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Affiliation(s)
- Linda Skibsted Kornerup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Henning Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | | | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Gitte Dam
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
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Neff G, Zachry W. Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic Impact of Rifaximin. PHARMACOECONOMICS 2018; 36:809-822. [PMID: 29651649 PMCID: PMC5999147 DOI: 10.1007/s40273-018-0641-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND Hepatic encephalopathy (HE), a common neurologic complication in cirrhosis, is associated with substantial disease and economic burden. Rifaximin is a non-systemic antibiotic that reduces the risk of overt HE recurrence and overt HE-related hospitalizations. OBJECTIVE Our objective was to provide an overview of the direct HE-related costs and cost benefits of rifaximin, lactulose, and rifaximin plus lactulose. METHODS A systematic review of PubMed and relevant meeting abstracts was conducted to identify publications since 1 January 2007 reporting economic data related to HE and rifaximin and/or lactulose. Further, a public database and published literature were used to estimate current costs of hospitalization for overt HE, and potential cost savings of HE-related hospitalizations with rifaximin. The methodological quality of included studies was evaluated using the Drummond checklist. RESULTS A total of 16 reports were identified for inclusion in the systematic review. Globally, HE-related direct costs ranged from $US5370 to $US50,120 annually per patient. Rifaximin was associated with shorter hospital stays and reduced healthcare costs. Rifaximin also has the potential to reduce overt HE-related hospitalization risk by 50% compared with lactulose. Rifaximin was shown to have a favourable pharmacoeconomic profile compared with lactulose (based on the incremental cost-effectiveness ratio). CONCLUSIONS In addition to its clinical benefits (e.g. reduction in the risk of recurrence of overt HE, overt HE-related hospitalizations, favourable adverse event profile), economic data are favourable for the use of rifaximin in patients with a history of overt HE.
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Affiliation(s)
- Guy Neff
- Florida Research Institute, Florida Digestive Health Specialists, Lakewood Ranch, FL, USA.
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Sun Q, Fan W, Ye J, Han P. Abnormal Regional Homogeneity and Functional Connectivity of Baseline Brain Activity in Hepatitis B Virus-Related Cirrhosis With and Without Minimal Hepatic Encephalopathy. Front Hum Neurosci 2018; 12:245. [PMID: 29988437 PMCID: PMC6024159 DOI: 10.3389/fnhum.2018.00245] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 05/29/2018] [Indexed: 12/16/2022] Open
Abstract
Background and Aims: Abnormalities in neural activity have been reported in cirrhosis with minimal hepatic encephalopathy (MHE). However, little is known about the neurophysiological mechanisms in this disorder. We aimed to investigate the altered patterns of regional synchronization and functional connections in hepatitis B virus-related cirrhosis (HBV-RC) patients with and without MHE using both regional homogeneity (ReHo) and region of interest (ROI)-based functional connectivity (FC) computational methods. Methods: Data of magnetic resonance imaging scans were collected from 30 HBV-RC patients with MHE, 32 HBV-RC patients without MHE (NMHE) and 64 well-matched controls. Several regions showing differences in ReHo after one-way analysis of variance (ANOVA) were defined as ROIs for FC analysis. Next, post hoc t-tests were applied to calculate the group differences in ReHo and FC (false discovery rate (FDR) correction, p < 0.05). Correlations between clinical variables and the altered ReHo and FC were then assessed in patient groups. Results: Across three groups, significant ReHo differences were found in nine ROI regions mainly within the visual network (VN), dorsal attention network (DAN), somatomotor network (SMN), fronto parietal control (FPC) network and thalamus. Compared with healthy controls (HC), the MHE group exhibited abnormal FC mainly between the right calcarine (CAL.R) and middle frontal gyrus (MFG.L)/right thalamus. The MHE patients showed increased FC between the MFG.L and CAL.R compared to NMHE patients. Disease duration of MHE patients was positively correlated with increased mean ReHo values in the right fusiform gyrus (FFG); psychometric hepatic encephalopathy score (PHES) test scores were negatively correlated with increased FC between MFG.L and CAL.R and positively correlated with reduced FC between the CAL.R and THA.R. For NMHE patients, the mean ReHo values in the right frontal pole were positively correlated with disease duration and positively correlated with the PHES scores. Conclusion: Our results exhibited that the functional brain modifications in patients with and without MHE are characterized by compound alterations in local coherence and functional connections in the VN, SMN, DAN, FPC networks and thalamus by using a combination of ReHo and ROI-based FC analysis. These functional imaging changes are correlated with disease duration/PHES. This study helped us gain a better understanding of the features of brain network modifications in cirrhosis.
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Affiliation(s)
- Qing Sun
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenliang Fan
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin Ye
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Han
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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26
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Suraweera D, Sundaram V, Saab S. Evaluation and Management of Hepatic Encephalopathy: Current Status and Future Directions. Gut Liver 2017; 10:509-19. [PMID: 27377741 PMCID: PMC4933409 DOI: 10.5009/gnl15419] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 08/31/2015] [Indexed: 12/18/2022] Open
Abstract
Hepatic encephalopathy is a spectrum of neurocognitive manifestations often seen in patients with liver injury or rarely in patients with portosystemic shunting without liver injury. It can be divided into minimal (covert) hepatic encephalopathy and overt hepatic encephalopathy, depending on the severity. Patients with hepatic encephalopathy have compromised clinical outcomes, decreased quality of life, and increased healthcare utilization, often resulting in a heavy financial and personal burden on caregivers. The diagnosis remains largely clinical, with the exclusion of possible other causes for the altered mental status. Current treatment strategies include nonabsorbable disaccharides and antibiotics. This review will focus on the diagnosis, management and clinical impact of hepatic encephalopathy.
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Affiliation(s)
| | - Vinay Sundaram
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sammy Saab
- 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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27
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Chen HJ, Shi HB, Jiang LF, Li L, Chen R. Disrupted topological organization of brain structural network associated with prior overt hepatic encephalopathy in cirrhotic patients. Eur Radiol 2017; 28:85-95. [PMID: 28667481 DOI: 10.1007/s00330-017-4887-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 05/04/2017] [Accepted: 05/10/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To investigate structural brain connectome alterations in cirrhotic patients with prior overt hepatic encephalopathy (OHE). METHODS Seventeen cirrhotic patients with prior OHE (prior-OHE), 18 cirrhotic patients without prior OHE (non-prior-OHE) and 18 healthy controls (HC) underwent diffusion tensor imaging. Neurocognitive functioning was assessed with Psychometric Hepatic Encephalopathy Score (PHES). Using a probabilistic fibre tracking approach, we depicted the whole-brain structural network as a connectivity matrix of 90 regions (derived from the Automated Anatomic Labeling atlas). Graph theory-based analyses were performed to analyse topological properties of the brain network. RESULTS The analysis of variance showed significant group effects on several topological properties, including network strength, global efficiency and local efficiency. A progressive decrease trend for these metrics was found from non-prior-OHE to prior-OHE, compared with HC. Among the three groups, the regions with altered nodal efficiency were mainly distributed in the frontal and occipital cortices, paralimbic system and subcortical regions. The topological metrics, such as network strength and global efficiency, were correlated with PHES among cirrhotic patients. CONCLUSIONS The cirrhotic patients developed structural brain connectome alterations; this is aggravated by prior OHE episode. Disrupted topological organization of the brain structural network may account for cognitive impairments related to prior OHE. KEY POINTS • Altered structural brain connectome is found in cirrhotic patients. • Structural brain connectome alterations could be aggravated by prior-OHE episode. • Altered structural brain connectome may account for cognitive impairments associated with prior OHE.
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Affiliation(s)
- Hua-Jun Chen
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China. .,Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Hai-Bin Shi
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Long-Feng Jiang
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Lan Li
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Rong Chen
- Department of Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. .,Advanced Innovation Center for Intelligent Robots and Systems, Beijing Institute of Technology, Beijing, 100081, China.
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28
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Pflugrad H, Tryc AB, Goldbecker A, Strassburg CP, Barg-Hock H, Klempnauer J, Weissenborn K. Hepatic encephalopathy before and neurological complications after liver transplantation have no impact on the employment status 1 year after transplantation. World J Hepatol 2017; 9:519-532. [PMID: 28443157 PMCID: PMC5387364 DOI: 10.4254/wjh.v9.i10.519] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 01/23/2017] [Accepted: 03/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the impact of hepatic encephalopathy before orthotopic liver transplantation (OLT) and neurological complications after OLT on employment after OLT. METHODS One hundred and fourteen patients with chronic liver disease aged 18-60 years underwent neurological examination to identify neurological complications, neuropsychological tests comprising the PSE-Syndrome-Test yielding the psychometric hepatic encephalopathy score, the critical flicker frequency and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), completed a questionnaire concerning their occupation and filled in the short form 36 (SF-36) to assess health-related quality of life before OLT and 12 mo after OLT, if possible. Sixty-eight (59.6%) patients were recruited before OLT, while on the waiting list for OLT at Hannover Medical School [age: 48.7 ± 10.2 years, 45 (66.2%) male], and 46 (40.4%) patients were included directly after OLT. RESULTS Before OLT 43.0% of the patients were employed. The patients not employed before OLT were more often non-academics (employed: Academic/non-academic 16 (34.0%)/31 vs not employed 10 (17.6%)/52, P = 0.04), had more frequently a history of hepatic encephalopathy (HE) (yes/no; employed 15 (30.6%)/34 vs not employed 32 (49.2%)/33, P = 0.05) and achieved worse results in psychometric tests (RBANS sum score mean ± SD employed 472.1 ± 44.5 vs not employed 443.1 ± 56.7, P = 0.04) than those employed. Ten patients (18.2%), who were not employed before OLT, resumed work afterwards. The patients employed after OLT were younger [age median (range, min-max) employed 47 (42, 18-60) vs not employed 50 (31, 29-60), P = 0.01], achieved better results in the psychometric tests (RBANS sum score mean ± SD employed 490.7 ± 48.2 vs not employed 461.0 ± 54.5, P = 0.02) and had a higher health-related quality of life (SF 36 sum score mean ± SD employed 627.0 ± 138.1 vs not employed 433.7 ± 160.8; P < 0.001) compared to patients not employed after OLT. Employment before OLT (P < 0.001), age (P < 0.01) and SF-36 sum score 12 mo after OLT (P < 0.01) but not HE before OLT or neurological complications after OLT were independent predictors of the employment status after OLT. CONCLUSION HE before and neurological complications after OLT have no impact on the employment status 12 mo after OLT. Instead younger age and employment before OLT predict employment one year after OLT.
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Affiliation(s)
- Henning Pflugrad
- Henning Pflugrad, Anita B Tryc, Annemarie Goldbecker, Karin Weissenborn, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
| | - Anita B Tryc
- Henning Pflugrad, Anita B Tryc, Annemarie Goldbecker, Karin Weissenborn, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
| | - Annemarie Goldbecker
- Henning Pflugrad, Anita B Tryc, Annemarie Goldbecker, Karin Weissenborn, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
| | - Christian P Strassburg
- Henning Pflugrad, Anita B Tryc, Annemarie Goldbecker, Karin Weissenborn, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
| | - Hannelore Barg-Hock
- Henning Pflugrad, Anita B Tryc, Annemarie Goldbecker, Karin Weissenborn, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
| | - Jürgen Klempnauer
- Henning Pflugrad, Anita B Tryc, Annemarie Goldbecker, Karin Weissenborn, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
| | - Karin Weissenborn
- Henning Pflugrad, Anita B Tryc, Annemarie Goldbecker, Karin Weissenborn, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
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29
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Nardelli S, Allampati S, Riggio O, Mullen KD, Prakash R, Gioia S, Unser A, White MB, Fagan AC, Wade JB, Farcomeni A, Gavis EA, Bajaj JS. Hepatic Encephalopathy Is Associated with Persistent Learning Impairments Despite Adequate Medical Treatment: A Multicenter, International Study. Dig Dis Sci 2017; 62:794-800. [PMID: 28039670 DOI: 10.1007/s10620-016-4425-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 12/16/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatic encephalopathy (HE) is considered reversible regarding mental status but may not be cognitively in single-center studies. AIM To evaluate persistence of learning impairment in prior HE compared to those who never experienced HE (no-HE) in a multicenter study. METHODS A total of 174 outpatient cirrhotics from three centers (94 Virginia, 30 Ohio, and 50 Rome; 36 prior HE) underwent psychometric hepatic encephalopathy score (PHES) and inhibitory control (ICT) testing at baseline and then at least 7 days apart. ICT learning (change in 2nd half lures compared to 1st half) was compared between patient groups at both visits. Change in the PHES individual sub-tests and total score between visits was compared in both groups. US versus Italian trends were also analyzed. RESULTS HE patients had worse PHES and ICT results compared to no-HE patients at baseline. Significant improvement (1st half 7.1 vs. 2nd half 6.2, p < 0.0001) was observed in no-HE, but not in HE (1st half 7.9 vs. 2nd half 7.8, p = 0.1) at baseline. At retesting (median 20 days later), no-HE patients continued with significant learning (1st half 6.0 vs. 2nd half 5.4, p < 0.0001), while HE patients again did not improve (1st half 7.8 vs. 2nd half 6.9, p = 0.37). Between visits, no-HE patients improved significantly on four PHES sub-tests and overall score, while HE patients only improved on two sub-tests with similar overall PHES score. Trends were similar between US and Italian subjects. CONCLUSION In this multicenter study, prior HE patients showed persistent significant learning impairment compared to those without prior HE, despite adequate medical therapy. This persistent change should increase efforts to reduce the first HE episode.
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Affiliation(s)
- Silvia Nardelli
- Division of Gastroenterology, Sapienza University of Rome, Rome, Italy
| | - Sanath Allampati
- Division of Gastroenterology, Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Oliviero Riggio
- Division of Gastroenterology, Sapienza University of Rome, Rome, Italy
| | - Kevin D Mullen
- Division of Gastroenterology, Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Ravi Prakash
- Division of Gastroenterology, Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Stefania Gioia
- Division of Gastroenterology, Sapienza University of Rome, Rome, Italy
| | - Ariel Unser
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, 23249, USA
| | - Melanie B White
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, 23249, USA
| | - Andrew C Fagan
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, 23249, USA
| | - James B Wade
- Department of Psychiatry, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Alessio Farcomeni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Edith A Gavis
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, 23249, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, 23249, USA.
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30
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Ahluwalia V, Wade JB, White MB, Gilles HS, Heuman DM, Fuchs M, Gavis EA, Fagan A, Tinsley F, Ganapathy D, Thacker LR, Sterling RK, Stravitz RT, Puri P, Sanyal AJ, Siddiqui MS, Matherly S, Luketic V, Steinberg J, Moeller FG, Bajaj JS. Liver transplantation significantly improves global functioning and cerebral processing. Liver Transpl 2016; 22:1379-90. [PMID: 27339647 PMCID: PMC5036999 DOI: 10.1002/lt.24498] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 06/01/2016] [Accepted: 06/13/2016] [Indexed: 01/13/2023]
Abstract
The functional basis of cognitive and quality of life changes after liver transplant is unclear. We aimed to evaluate the neurometabolic and functional brain changes as modulators of cognition and quality of life after transplant in patients with cirrhosis who were with/without pretransplant cognitive impairment and hepatic encephalopathy (HE). Patients with cirrhosis underwent detailed cognitive and quality of life assessment at enrollment and 6 months after transplant. A subset underwent brain magnetic resonance imaging (functional magnetic resonance imaging [fMRI], diffusion tensor imaging [DTI], and magnetic resonance spectroscopy [MRS]) before and after transplant. Changes before and after transplant were analyzed in all patients and by dividing groups in those with/without pretransplant cognitive impairment or with/without pretransplant HE. MRS evaluated ammonia-related metabolites; fMRI studied brain activation for correct lure inhibition on the inhibitory control test; and DTI studied white matter integrity. Sixty-six patients (mean Model for End-Stage Liver Disease score, 21.8; 38 HE patients and 24 cognitively impaired [CI] patients) were enrolled. Quality of life was significantly worse in CI and HE groups before transplant, which improved to a lesser extent in those with prior cognitive impairment. In the entire group after transplant, there was (1) significantly lower brain activation needed for lure inhibition (shown on fMRI); (2) reversal of pretransplant ammonia-associated changes (shown on MRS); and (3) improved white matter integrity (shown on DTI). Importantly, study findings suggest that pretransplant cognitive impairment serves as a marker for clinical outcomes. Regardless of pretransplant history of HE, it was the pretransplant cognitive impairment that was predictive of both posttransplant cognitive and psychosocial outcomes. Therefore, when working with patients and their families, a clinician may rely on the pretransplant cognitive profile to develop expectations regarding posttransplant neurobehavioral recovery. We conclude that functional brain changes after liver transplant depend on pretransplant cognitive impairment and are ultimately linked with posttransplant cognition and quality of life in cirrhosis. Liver Transplantation 22 1379-1390 2016 AASLD.
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Affiliation(s)
- Vishwadeep Ahluwalia
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - James B Wade
- Psychiatry, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Melanie B White
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - HoChong S Gilles
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Douglas M Heuman
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Michael Fuchs
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Edith A Gavis
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Andrew Fagan
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | | | - Dinesh Ganapathy
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Leroy R Thacker
- Biostatistics, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Richard K Sterling
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - R Todd Stravitz
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Puneet Puri
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Arun J Sanyal
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Muhammad S Siddiqui
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Scott Matherly
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Velimir Luketic
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Joel Steinberg
- Psychiatry, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - F Gerard Moeller
- Psychiatry, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Jasmohan S Bajaj
- Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
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31
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Bajaj JS, White MB, Unser AB, Ganapathy D, Fagan A, Gavis EA, Sterling RK, Heuman DM, Matherly S, Puri P, Sanyal AJ, Luketic V, Fuchs M, Siddiqui MS, Stravitz RT, John B, Thacker LR, Wade JB. Cirrhotic patients have good insight into their daily functional impairment despite prior hepatic encephalopathy: comparison with PROMIS norms. Metab Brain Dis 2016; 31:1199-203. [PMID: 27344317 PMCID: PMC5033693 DOI: 10.1007/s11011-016-9860-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 06/19/2016] [Indexed: 01/05/2023]
Abstract
Health-related quality of life (HRQOL) is an important determinant of prognosis in cirrhosis and hepatic encephalopathy (HE). However due to inherent cognitive dysfunction, insight into HRQOL severity in patients with liver disease may be impaired. To assess insight into HRQOL using PROMIS tools compared to norms in cirrhotic patients. PROMIS tools are validated HRQOL instruments that test the domains of anger, anxiety, depression, physical function, pain behavior/impact, sleep disturbances/impairment, and social activities/roles, compared to US-norms. Patients were administered the PROMIS tools, the results of which were reviewed using a visual comparison with thed norms. Then two Likert scales from 0 to 10 per domain were administered that inquired about (1) Surprise Intensity: 0-4: not surprised, 5-10: surprised; and (2) Expectancies: 0-4: results better than expected, 5:10: as/worse than expected. Comparisons between HE/no-HE were also performed. 203 cirrhotic patients (57 yrs., 62 % men, MELD 12, 83 HE) were included. All HE patients were controlled on therapy. Prior HE patients were significantly impaired on all PROMIS domains (p < 0.01) except anger, compared to the re st. The majority (76-85 %) were not surprised with their placement vis-à-vis the norms. Similarly, a majority (59-61 %) thought their results were worse or as expected. However, a third of patients found that their PROMIS results were better than expected. Prior HE status did not significantly impact expectations or surprise based on placement with the norms. The majority of cirrhotic patients, regardless of prior HE, have good insight regarding their HRQOL issues.
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Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA.
| | - Melanie B White
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Ariel B Unser
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Dinesh Ganapathy
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Andrew Fagan
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Edith A Gavis
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Richard K Sterling
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Douglas M Heuman
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Scott Matherly
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Puneet Puri
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Velimir Luketic
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Michael Fuchs
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Muhammad S Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - R Todd Stravitz
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Binu John
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia, 23249, USA
| | - Leroy R Thacker
- Biostatistics, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - James B Wade
- Psychiatry, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
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Lucidi C, Ginanni Corradini S, Abraldes JG, Merli M, Tandon P, Ferri F, Parlati L, Lattanzi B, Poli E, Di Gregorio V, Farcomeni A, Riggio O. Hepatic encephalopathy expands the predictivity of model for end-stage liver disease in liver transplant setting: Evidence by means of 2 independent cohorts. Liver Transpl 2016; 22:1333-42. [PMID: 27434824 DOI: 10.1002/lt.24517] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 06/13/2016] [Accepted: 06/28/2016] [Indexed: 02/07/2023]
Abstract
Despite its documented prognostic relevance, hepatic encephalopathy (HE) is not considered in liver transplantation (LT) due to its possible poor objectivity. To override this problem, we aimed to analyze if an objective diagnosis of HE may confer additional mortality risk beyond MELD. Study and validation cohorts of patients with cirrhosis were considered in Italy and Canada, respectively. Patients were considered to be HE+ if an episode of overt HE was documented in a hospitalization. Of the 486 patients enrolled in Italy, 184 (38%) were HE+. During the 6-month follow-up, 77 patients died and 50 underwent transplantation. The 6-month mortality of HE+ versus HE- patients was significantly higher (P < 0.001). Model for End-Stage Liver Disease (MELD; subdistribution hazard ratio [sHR], 1.2; 95% confidence interval [CI], 1.1-1.2; P < 0.001), HE+ (sHR, 3.6; 95% CI, 1.8-7.1; P < 0.001), and sodium (sHR, 0.9; 95% CI, 0.8-0.9; P < 0.001) were independent predictors of 6-month mortality. In HE+ patients, short-term mortality increased across the entire MELD spectrum (range, 6-40). The results were unchanged by including or excluding patients with hepatocellular carcinoma or stratifying patients according to HE characteristics. The higher 6-month mortality of HE+ versus HE- patients was confirmed also in the Canadian cohort (P < 0.001; n = 300, 33% HE+; 33 died, 104 transplanted). A similar and statistically significant C-index increase derived by the incorporation of HE in MELD was observed both in the Italian (from 0.67 to 0.75) and Canadian (from 0.69 to 0.74) cohorts. A score based on MELD plus 7 points (95% CI, 4-10) for HE+ patients optimally predicted 6-month mortality in the 2 cohorts. According to the net reclassification index, by not considering HE, 29% of overall patients were misclassified by MELD score. In conclusion, the incorporation of HE in MELD score might improve the listing and allocation policy in LT. Liver Transplantation 22 1333-1342 2016 AASLD.
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Affiliation(s)
- Cristina Lucidi
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy
| | | | - Juan G Abraldes
- Cirrhosis Care Clinic, Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, Canada
| | - Manuela Merli
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy
| | - Puneeta Tandon
- Cirrhosis Care Clinic, Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, Canada
| | - Flaminia Ferri
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy
| | - Lucia Parlati
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy
| | - Barbara Lattanzi
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy
| | - Edoardo Poli
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy
| | - Vincenza Di Gregorio
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy
| | - Alessio Farcomeni
- Public Health and Infectious Diseases, "Sapienza", University of Rome, Rome, Italy
| | - Oliviero Riggio
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy.
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Yoshimura E, Ichikawa T, Miyaaki H, Taura N, Miuma S, Shibata H, Honda T, Takeshima F, Nakao K. Screening for minimal hepatic encephalopathy in patients with cirrhosis by cirrhosis-related symptoms and a history of overt hepatic encephalopathy. Biomed Rep 2016; 5:193-198. [PMID: 27446540 DOI: 10.3892/br.2016.702] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 05/30/2016] [Indexed: 02/06/2023] Open
Abstract
The diagnosis of minimal hepatic encephalopathy (MHE) is more difficult in comparison to the diagnosis of overt hepatic encephalopathy (OHE), as patients with MHE do not exhibit overt neurological deficits and must be diagnosed using specialized equipment. However, identifying MHE is critical for patients with cirrhosis, and a simple screening test is required. The present study aimed to evaluate the associations between MHE, clinical characteristics and questionnaire items regarding sleep disturbances and cirrhosis-related symptom score (CSS). A total of 91 patients who had cirrhosis without OHE were evaluated using various questionnaires [i.e., CSS, Epworth Sleepiness Scale, the Japanese version of the Pittsburgh Sleep Quality Index (PSQI) and the Japanese 36-item short-form health survey (SF-36)]. MHE was diagnosed using the neuropsychological test. MHE was associated with severe liver damage, which was indicated by liver damage markers and a history of OHE. In addition, MHE was associated with the CSS, PSQI and SF-36 results. The multivariate analyses revealed that a history of OHE was the factor that was the most strongly associated with MHE. Among patients without a history of OHE, MHE was most strongly associated with CSS, although it was also associated with severe liver damage and platelet counts. A prediction score (calculated using a history of OHE and CSS) provided an area under the receiver operating characteristic curve of 0.738 and a sensitivity of 0.671 for identifying MHE. In conclusion, a history of OHE and CSS may be useful for identifying MHE in patients with cirrhosis.
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Affiliation(s)
- Emi Yoshimura
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan
| | - Tatsuki Ichikawa
- Department of Gastroenterology, Nagasaki Harbor Medical Center, City Hospital, Nagasaki 850-8555, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan
| | - Naota Taura
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan
| | - Hidataka Shibata
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan
| | - Takuya Honda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan
| | - Fuminao Takeshima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8501, Japan
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Lee Y, Kim C, Suk KT, Choi HC, Bang CS, Yoon JH, Baik GH, Kim DJ, Jang MU, Sohn JH. Differences in cognitive function between patients with viral and alcoholic compensated liver cirrhosis. Metab Brain Dis 2016; 31:369-76. [PMID: 26563125 DOI: 10.1007/s11011-015-9761-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 11/06/2015] [Indexed: 12/11/2022]
Abstract
As alcohol induces change in frontal cortex primarily involved in cognition, cognitive function may be different between viral and alcoholic liver cirrhosis (LC). This study aimed to determine the differences of cognitive function between viral and alcoholic compensated LC. From October 2011 to March 2013, 80 patients (viral: 37; alcohol: 43) with compensated LC were prospectively enrolled. Neuropsychological functions including attention, language, visuospatial, verbal memory, visual memory, and frontal/executive function were evaluated between two groups and compared with age-matched normal group (n = 1000). Cumulative incidence rate of overt hepatic encephalopathy (HE) was calculated. In the comparison with normal group, both two groups showed decreased memory function, frontal/executive function, and Korea-Mini Mental Status Examination. In the analysis of two groups, memory function by Verbal Learning Test (recognition: 20.1 ± 3.6 and 17.8 ± 4.8, p = 0.022), visuospatial function by Ray-Complex Figure Copy Test (recognition: 19.0 ± 2.6 and 17.3 ± 4.0, p = 0.043), frontal/executive function by Controlled Oral Ward Association (semantic: 17.1 ± 6.9 and 12.7 ± 6.9, p = 0.004), and the Korea-Mini Mental Status Examination (27.5 ± 1.9 and 26.2 ± 3.1, p = 0.03) showed low scores in alcoholic compensated LC patients. The 1-, 2-, and 3-year cumulative incidence rates of overt HE were 23%, 26%, and 26% and 33%, 43%, and 49% in the viral and alcoholic compensated LC group, respectively (p = 0.033). Impaired memory and frontal lobe executive functions and early development of overt HE were more common in patients with alcoholic LC. For patients with alcoholic LC, more integrated tests for early detection of minimal HE and intensive treatment should be considered to prevent overt HE.
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Affiliation(s)
- Yunhyeong Lee
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Chulho Kim
- Department of Neurology, Hallym University College of Medicine, Chuncheon, South Korea
| | - Ki Tae Suk
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
- Department of Medicine, Columbia University, New York, NY, USA
- Department in Internal Medicine, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon,, Gyo-dong, 200-704, South Korea
| | - Hui Chul Choi
- Department of Neurology, Hallym University College of Medicine, Chuncheon, South Korea.
- Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Gyo-dong, 200-704, South Korea.
| | - Chang Seok Bang
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Jai Hoon Yoon
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Gwang Ho Baik
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Min Uk Jang
- Department of Neurology, Hallym University College of Medicine, Chuncheon, South Korea
| | - Jong Hee Sohn
- Department of Neurology, Hallym University College of Medicine, Chuncheon, South Korea
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Yadav SK, Gupta RK, Saraswat VA, Rangan M, Thomas MA, Rutella S, Danese S, Wang E, Marincola FM, Haris M. Reduced cortical thickness in patients with acute-on-chronic liver failure due to non-alcoholic etiology. J Transl Med 2015; 13:322. [PMID: 26444271 PMCID: PMC4596551 DOI: 10.1186/s12967-015-0679-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 09/24/2015] [Indexed: 12/30/2022] Open
Abstract
Background Acute-on-chronic liver failure (ACLF) is a form of liver disease with high short-term mortality. ACLF offers considerable potential to affect the cortical areas by significant tissue injury due to loss of neurons
and other supporting cells. We measured changes in cortical thickness and metabolites profile in ACLF patients following treatment, and compared it with those of age matched healthy volunteers. Methods For the cortical thickness analysis we performed whole brain high resolution T1-weighted magnetic resonance imaging (MRI) on 15 ACLF and 10 healthy volunteers at 3T clinical MR scanner. Proton MR Spectroscopy (1H MRS) was also performed to measure level of altered metabolites. Out of 15 ACLF patients 10 survived and underwent follow-up study after clinical recovery at 3 weeks. FreeSurfer program was used to quantify cortical thickness and LC- Model software was used to quantify absolute metabolites concentrations. Neuropsychological (NP) test was performed to assess the cognitive performance in follow-up ACLF patients compared to controls. Results Significantly reduced cortical thicknesses in multiple brain sites, and significantly decreased N-acetyl aspartate (NAA), myo-inositol (mI) and significantly increased glutamate/glutamine (glx) metabolites were observed in ACLF compared to those of controls at baseline study. Follow-up patients showed significant recovery in cortical thickness and Glx level, while NAA and mI were partially recovered compared to baseline study. When compared to controls, follow-up patients still showed reduced cortical thickness and altered metabolites level. Follow-up patients had abnormal neuropsychological (NP) scores compared to controls. Conclusions Neuronal loss as suggested by the reduced NAA, decreased cellular density due to increased cerebral hyperammonemia as supported by the increased glx level, and increased proinflammatory cytokines and free radicals may account for the reduced cortical thickness in ACLF patients. Presence of reduced cortical thickness, altered metabolites and abnormal NP test scores in post recovery subjects as compared to those of controls is associated with incomplete clinical recovery. The current imaging protocol can be easily implemented in clinical settings to evaluate and monitor brain tissue changes in patients with ACLF during the course of treatment.
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Affiliation(s)
- Santosh K Yadav
- Research Branch, Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar.
| | - Rakesh K Gupta
- Department of Radiology, Fortis Memorial Research Institute, Gurgaon, Haryana, India.
| | - Vivek A Saraswat
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
| | - Murali Rangan
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
| | - Michael A Thomas
- Department of Radiological Sciences, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, USA.
| | - Sergio Rutella
- Research Branch, Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar.
| | - Silvio Danese
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy.
| | - Ena Wang
- Research Branch, Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar.
| | | | - Mohammad Haris
- Research Branch, Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar.
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Abstract
Hepatic encephalopathy (HE) is a commonly encountered sequela of chronic liver disease and cirrhosis with significant associated morbidity and mortality. Although ammonia is implicated in the pathogenesis of HE, the exact underlying mechanisms still remain poorly understood. Its role in the urea cycle, astrocyte swelling, and glutamine and gamma-amino-n-butyric acid systems suggests that the pathogenesis is multifaceted. Greater understanding in its underlying mechanism may offer more targeted therapeutic options in the future, and thus further research is necessary to fully understand the pathogenesis of HE.
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Affiliation(s)
- Parth J Parekh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tulane University, New Orleans, LA, USA
| | - Luis A Balart
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tulane University, New Orleans, LA, USA.
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Füessl HS. [Hepatic encephalopathy causes permanent damage]. MMW Fortschr Med 2015; 157:27. [PMID: 25743291 DOI: 10.1007/s15006-015-2577-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
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