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Ali YO, Goble SR, Leventhal TM. Disparities and Outcomes of Physical Restraint Use in Hepatic Encephalopathy: A National Inpatient Assessment. Dig Dis Sci 2025; 70:146-153. [PMID: 39581898 DOI: 10.1007/s10620-024-08758-2] [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: 06/27/2024] [Accepted: 11/13/2024] [Indexed: 11/26/2024]
Abstract
BACKGROUND Physical restraints may be utilized in patients with hepatic encephalopathy with the intention to ensure patient safety. AIMS Determine if racial and socioeconomic disparities exist in restraint use for patients with hepatic encephalopathy and determine clinical efficacy of restraints in hepatic encephalopathy. METHODS We performed a cross-sectional retrospective study of hospitalizations for hepatic encephalopathy from 2016 to 2021 using the National Inpatient Sample. Patient race and income were assessed for associations with restraint use and restraints themselves were then assessed for associations with clinical outcomes including mortality. Separate analyses were performed for hospitalizations with and without invasive cares defined as the presence of ICD-10 codes for mechanical ventilation, gastric tube placement and/or central venous catheter placement. RESULTS Restraint use was documented in 2.4% of 228,430 hospitalizations. In hospitalizations without defined invasive cares, restraint use was increased in Black patients compared to White patients (aOR = 1.57, 95% CI 1.24-1.98, p < 0.001) while lower income was not independently associated with restraint use (1st vs. 4th quartile national income aOR = 0.98, p = 0.895). In hospitalizations that did not involve other defined invasive cares, physical restraint use was associated with higher mortality (aOR = 1.71, 95% CI 1.20-2.43, p = 0.003), whereas in hospitalizations where invasive cares were employed, physical restraint use was associated with reduced mortality (aOR = 0.55, 95% CI 0.40-0.77, p < 0.001). CONCLUSIONS Careful consideration of the necessity of restraints in hepatic encephalopathy hospitalizations without other invasive cares appears warranted as social disparities in restraint use and increased mortality were both found in this group.
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Affiliation(s)
- Yasmin O Ali
- Department of Medicine, Hennepin Healthcare, 730 South 8th Street, Minneapolis, MN, 55415, USA
| | - Spencer R Goble
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, MMC 36, 420 Delaware Street S.E., Minneapolis, MN, 55455, USA.
| | - Thomas M Leventhal
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, MMC 36, 420 Delaware Street S.E., Minneapolis, MN, 55455, USA
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Singh VV, Prasad SK, Acharjee A, Srivastava S, Acharjee P. Investigating cognitive impairments and hippocampal proteome alterations in aged male rats with TAA-Induced minimal hepatic encephalopathy. Biogerontology 2024; 26:30. [PMID: 39704865 DOI: 10.1007/s10522-024-10158-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/13/2024] [Indexed: 12/21/2024]
Abstract
The aging population faces a gradual decline in physical and mental capacities, with an increased risk of liver cirrhosis and chronic liver diseases leading to hepatic encephalopathy (HE). The intertwining of physiological manifestations of aging with the pathophysiology of HE significantly impairs cognitive ability, reduces quality of life, and increases mortality. Hence, effective therapeutic intervention is imperative. The present study investigated the impact of minimal HE (MHE) on cognitive impairment in an aged rat population by analyzing hippocampal proteome dynamics. For this purpose, an old MHE rat model was induced via thioacetamide. The label-free LC‒MS/MS method was employed to explore hippocampal proteomic changes and associated dysregulated biological pathways. A total of 1533 proteins were identified, and among these, 30 proteins were significantly differentially expressed (18 upregulated, and 12 downregulated). Three upregulated proteins, namely, fetuin-A, p23, and intersectin-1 were selected and validated for their increased expression via western blotting and immunofluorescence analysis, which confirmed the mass spectrometry results. These proteins have not been reported previously in MHE cases. We also identified the possible dysregulated biological pathways associated with the differentially expressed proteins via Metascape, a network analysis tool. We found that the differentially expressed proteins may be involved in the generation of precursor metabolites and energy, the neurotransmitter release cycle, positive regulation of dendritic spine development, chaperone-mediated protein folding and protein stabilization. This study highlights the potential mechanisms underlying neurological dysfunction in the aged population with MHE and identifies novel therapeutic targets for improved disease management.
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Affiliation(s)
- Vishal Vikram Singh
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Shambhu Kumar Prasad
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Arup Acharjee
- Molecular Omics Laboratory, Department of Zoology, University of Allahabad, Prayagraj, 211002, India.
| | - Sanjeeva Srivastava
- Department of Bioscience and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India
| | - Papia Acharjee
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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Bajaj JS, Pompili E, Caraceni P. The burden of hepatic encephalopathy and the use of albumin as a potential treatment. Ann Hepatol 2024; 30:101751. [PMID: 39631456 DOI: 10.1016/j.aohep.2024.101751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 09/30/2024] [Indexed: 12/07/2024]
Abstract
As a potential sequela of cirrhosis, hepatic encephalopathy (HE) significantly impacts the lives of patients and caregivers and places a substantial burden on the healthcare system. With an increasing incidence over time and a cumulative effect on cognition, HE adversely effects quality of life, morbidity and mortality in patients with cirrhosis. HE can range from minimal or covert (MHE/CHE) to overt and symptomatic (OHE). HE has profound impacts on the health and wellbeing of patients and their families and caregivers. Effective treatments could improve the quality of life for all those affected. In this article, we discuss the existing treatments for HE and focus on the potential role of albumin in the treatment of HE. Currently approved therapies for HE (lactulose and rifaximin) are focused on decreasing the formation of ammonia in the gastrointestinal tract. Among the many agents with alternative mechanisms being investigated for treatment of HE, albumin has been studied in clinical trials with acute (≤ 3 days), short-term (up to 2 weeks) prolonged (> 2 weeks) and long-term administration (months). Current studies indicate that acute or short-term administration of albumin does not provide significant benefit for patients with OHE. However, there is increasing evidence that prolonged or long-term albumin therapy can help improve cognition in OHE and prevent recurrence. Additional studies are needed to substantiate these positive findings for longer term administration of albumin in HE and to increase our comprehension of the pharmacologic basis of the effects of albumin.
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Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Central Virginia Healthcare System, Richmond, Virginia, USA.
| | - Enrico Pompili
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy; Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy; Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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Llansola M, Izquierdo-Altarejos P, Montoliu C, Mincheva G, Palomares-Rodriguez A, Pedrosa MA, Arenas YM, Felipo V. Role of peripheral inflammation in minimal hepatic encephalopathy. Metab Brain Dis 2024; 39:1667-1677. [PMID: 39177864 DOI: 10.1007/s11011-024-01417-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/16/2024] [Indexed: 08/24/2024]
Abstract
Many patients with liver cirrhosis show minimal hepatic encephalopathy (MHE) with mild cognitive impairment (MCI) and motor alterations that reduce their quality of life. Some patients with steatotic liver disease also suffer MCI. To design treatments to improve MHE/MCI it is necessary to understand the mechanisms by which liver disease induce them. This review summarizes studies showing that appearance of MHE/MCI is associated with a shift in the immunophenotype leading to an "autoimmune-like" form with increased pro-inflammatory monocytes, enhanced CD4 T and B lymphocytes activation and increased plasma levels of pro-inflammatory cytokines, including IL-17, IL-21, TNFα, IL-15 and CCL20. The contribution of peripheral inflammation to trigger MHE is supported by studies in animal models and by the fact that rifaximin treatment reverses MHE in around 60% of patients in parallel with reversal of the changes in peripheral inflammation. MHE does not improve in patients in which peripheral inflammation is not improved by rifaximin. The process by which peripheral inflammation induces MHE involves induction of neuroinflammation in brain, with activation of microglia and astrocytes and increased pro-inflammatory TNFα and IL-1β, which is observed in patients who died with steatotic liver disease (SLD) or liver cirrhosis and in animal models of MHE. Neuroinflammation alters glutamatergic and GABAergic neurotransmission, leading to cognitive and motor impairment. Transmission of peripheral alterations into the brain is mediated by infiltration in brain of extracellular vesicles from plasma and of cells from the peripheral immune system. Acting on any step of the process peripheral inflammation - neuroinflammation - altered neurotransmission may improve MHE.
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Affiliation(s)
- Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | | | - Carmina Montoliu
- Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - Gergana Mincheva
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | | | - María A Pedrosa
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Yaiza M Arenas
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
- Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
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Johnson CD, Stevens CM, Bennett MR, Litch AB, Rodrigue EM, Quintanilla MD, Wallace E, Allahyari M. The Role of Vitamin D Deficiency in Hepatic Encephalopathy: A Review of Pathophysiology, Clinical Outcomes, and Therapeutic Potential. Nutrients 2024; 16:4007. [PMID: 39683402 DOI: 10.3390/nu16234007] [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: 10/29/2024] [Revised: 11/18/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric condition frequently associated with cirrhosis and portosystemic shunting (PSS). It imposes a significant clinical and economic burden, with increasing attention toward identifying modifiable factors that could improve outcomes. Emerging evidence suggests that vitamin D deficiency (VDD), prevalent in patients with cirrhosis, may contribute to the development and severity of HE. This review explores the association between VDD and HE by analyzing the underlying pathophysiology, including oxidative stress, ammonia accumulation, and impaired hepatic function. Additionally, we summarize recent studies highlighting the correlation between low serum 25-hydroxy vitamin D (25-OHD) levels and worsening grades of HE. Despite strong observational data, interventional studies on vitamin D (VD) supplementation for HE remains limited. Current evidence suggests that VD's antioxidant properties may alleviate oxidative stress in HE, with potential benefits in mitigating disease severity. Future research should focus on longitudinal studies and randomized controlled trials to evaluate the clinical impact of VD supplementation on HE outcomes and explore VD's role in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedures. Understanding the therapeutic potential of VD could lead to improved management strategies for HE and cirrhotic patients at large.
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Affiliation(s)
- Coplen D Johnson
- School of Medicine, Louisiana State University Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA
| | - Christopher M Stevens
- School of Medicine, Louisiana State University Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA
| | - Matthew R Bennett
- School of Medicine, Louisiana State University Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA
| | - Adam B Litch
- School of Medicine, Louisiana State University Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA
| | - Eugenie M Rodrigue
- School of Medicine, Louisiana State University Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA
| | - Maria D Quintanilla
- School of Medicine, Louisiana State University Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA
| | - Eric Wallace
- Department of Radiology, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA
| | - Massoud Allahyari
- Department of Radiology, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA
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Prasad SK, Singh VV, Acharjee A, Acharjee P. Elucidating hippocampal proteome dynamics in moderate hepatic encephalopathy rats: insights from high-resolution mass spectrometry. Exp Brain Res 2024; 242:1659-1679. [PMID: 38787444 DOI: 10.1007/s00221-024-06853-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
Hepatic encephalopathy (HE) is a debilitating neurological disorder associated with liver failure and characterized by impaired brain function. Decade-long studies have led to significant advances in our understanding of HE; however, effective therapeutic management of HE is lacking, and HE continues to be a significant cause of morbidity and mortality in patients, underscoring the need for continued research into its pathophysiology and treatment. Accordingly, the present study provides a comprehensive overview aimed at elucidating the molecular underpinnings of HE and identifying potential therapeutic targets. A moderate-grade HE model was induced in rats using thioacetamide, which simulates the liver damage observed in patients, and its impact on cognitive function, neuronal arborization, and cellular morphology was also evaluated. We employed label-free LC-MS/MS proteomics to quantitatively profile hippocampal proteins to explore the molecular mechanism of HE pathogenesis; 2175 proteins were identified, 47 of which exhibited significant alterations in moderate-grade HE. The expression of several significantly upregulated proteins, such as FAK1, CD9 and Tspan2, was further validated at the transcript and protein levels, confirming the mass spectrometry results. These proteins have not been previously reported in HE. Utilizing Metascape, a tool for gene annotation and analysis, we further studied the biological pathways integral to brain function, including gliogenesis, the role of erythrocytes in maintaining blood-brain barrier integrity, the modulation of chemical synaptic transmission, astrocyte differentiation, the regulation of organ growth, the response to cAMP, myelination, and synaptic function, which were disrupted during HE. The STRING database further elucidated the protein‒protein interaction patterns among the differentially expressed proteins. This study provides novel insights into the molecular mechanisms driving HE and paves the way for identifying novel therapeutic targets for improved disease management.
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Affiliation(s)
- Shambhu Kumar Prasad
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Vishal Vikram Singh
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Arup Acharjee
- Department of Zoology, University of Allahabad, Prayagraj, 211002, India.
| | - Papia Acharjee
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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Becher A, Acke E, Serrano G, Kiefer I, Alef M, von Bomhard W, Heilmann RM. Evaluation of the Blood Neutrophil-to-Lymphocyte Ratio (NLR) as a Diagnostic and Prognostic Biomarker in Dogs with Portosystemic Shunt. Vet Sci 2024; 11:80. [PMID: 38393098 PMCID: PMC10893402 DOI: 10.3390/vetsci11020080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 01/29/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
The neutrophil-to-lymphocyte ratio (NLR) can help in assessing inflammatory diseases, sepsis, and chronic hepatic conditions in humans. Dogs with congenital portosystemic shunts (PSSs) have signs of generalized inflammation, and the clinical signs can overlap with other conditions, including hypoadrenocorticism (HOC). Thus, the potential diagnostic and prognostic value of leukocyte ratios as surrogate markers was assessed in a retrospective case-control study including 106 dogs diagnosed with PSSs. The disease control groups were dogs with parenchymal hepatopathy (PH; n = 22) or HOC (n = 31). In the PSS dogs, the blood NLRs were associated with the severity of systemic inflammation but not with the shunt type, hepatoencephalopathy, systemic infection, or hypoglycemia. The baseline NLRs did not differ between the three disease groups, between medically and surgically treated PSS dogs, or between those with successful PSS ligation and dogs experiencing peri-/post-surgical complications. However, dogs requiring two consecutive surgical interventions had significantly higher NLRs, and an NLR of <2.53 distinguished dogs with successful shunt ligation in one surgery from those requiring two consecutive surgeries for PSS closure. The blood NLR might be a useful clinicopathologic variable in PSS, but its value in helping differentiate PSS from HOC cases appears low. Integrating the NLR into a diagnostic algorithm may allow for a prediction of the number of surgical interventions required.
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Affiliation(s)
- Anja Becher
- Department for Small Animals, Veterinary Teaching Hospital, College of Veterinary Medicine, University of Leipzig, 04103 Leipzig, SN, Germany; (A.B.); (E.A.); (I.K.); (M.A.)
| | - Els Acke
- Department for Small Animals, Veterinary Teaching Hospital, College of Veterinary Medicine, University of Leipzig, 04103 Leipzig, SN, Germany; (A.B.); (E.A.); (I.K.); (M.A.)
- IDEXX Vet Med Labor GmbH, 70806 Kornwestheim, BW, Germany
| | - Gonçalo Serrano
- Small Animal Department, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium;
- AniCura Haaglanden Specialist Referral Centre, 2288 EZ Rijswijk, The Netherlands
| | - Ingmar Kiefer
- Department for Small Animals, Veterinary Teaching Hospital, College of Veterinary Medicine, University of Leipzig, 04103 Leipzig, SN, Germany; (A.B.); (E.A.); (I.K.); (M.A.)
| | - Michaele Alef
- Department for Small Animals, Veterinary Teaching Hospital, College of Veterinary Medicine, University of Leipzig, 04103 Leipzig, SN, Germany; (A.B.); (E.A.); (I.K.); (M.A.)
| | - Wolf von Bomhard
- Antech Specialty Center for Veterinary Pathology, 81477 Munich, BY, Germany;
| | - Romy M. Heilmann
- Department for Small Animals, Veterinary Teaching Hospital, College of Veterinary Medicine, University of Leipzig, 04103 Leipzig, SN, Germany; (A.B.); (E.A.); (I.K.); (M.A.)
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Zahr N, Sullivan E, Pfefferbaum A. [WITHDRAWN] Serum biomarkers of liver fibrosis identify changes in striatal metabolite levels. RESEARCH SQUARE 2024:rs.3.rs-2729490. [PMID: 37034697 PMCID: PMC10081358 DOI: 10.21203/rs.3.rs-2729490/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.
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Casanova-Ferrer F, Gallego JJ, Fiorillo A, Urios A, Ríos MP, León JL, Ballester MP, Escudero-García D, Kosenko E, Belloch V, Montoliu C. Improved cognition after rifaximin treatment is associated with changes in intra- and inter-brain network functional connectivity. J Transl Med 2024; 22:49. [PMID: 38217008 PMCID: PMC10787503 DOI: 10.1186/s12967-023-04844-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 12/29/2023] [Indexed: 01/14/2024] Open
Abstract
BACKGROUND Rifaximin is a non-reabsorbable antibiotic which acts at gut level, and improves cognition and inflammatory parameters in minimal hepatic encephalopathy (MHE) patients, but not all patients show the same level of response. This study aims to assess brain activity, both within and between brain networks, following rifaximin treatment, considering the differences between response groups as well. METHODS Twenty-two healthy controls and 53 patients with cirrhosis (22 without and 31 with MHE, diagnosed by Psychometric Hepatic Encephalopathy Score, PHES) performed psychometric, attention and coordination tests, and blood inflammatory parameters were measured. Resting-state functional magnetic resonance imaging (fMRI) acquisitions were performed on controls and MHE patients. Eighteen MHE patients underwent a rifaximin treatment for 6 months, after which all measures were repeated. fMRI images were analysed and changes after treatment were assessed. RESULTS After rifaximin treatment, 13 patients improved their PHES score (Responder patients) while 5 did not (Non-responder patients). No significant decrease in blood ammonia was observed after rifaximin treatment, but there was a decrease in plasma inflammatory cytokines in responder patients. A global effect of rifaximin was detected on the sensorimotor and fronto-parietal networks. Responder patients showed a relative increase of thalamic network connectivity in comparison to non-responder patients. Before treatment, responder and non-responder patients showed connectivity differences in basal ganglia network. The connection of the sensorimotor and thalamic networks between them and with other networks suffered changes after treatment. These connections between networks mostly decreased after treatment. All changes and differences showed a significant level of correlation with the performance of psychometric tests and the blood levels of inflammatory biomarkers. CONCLUSIONS There was an improvement of the communication between executive, motor and attention-related brain areas, and their functional independence following rifaximin treatment. Patients who respond also show a less deteriorated connection involved in these functions before treatment. Results suggest that the improved inflammatory state of MHE patients, following rifaximin treatment would favour the observed changes in brain function and enhanced cognitive performance.
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Affiliation(s)
- Franc Casanova-Ferrer
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - Juan-José Gallego
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - Alessandra Fiorillo
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - Amparo Urios
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - María-Pilar Ríos
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova de Valencia, Valencia, Spain
| | - José Luis León
- Universitats Neurorradiology Unit, Ascires Biomedical Group, Valencia, Spain
| | - María-Pilar Ballester
- Servicio de Medicina Digestiva, Hospital Clinico Universitario de Valencia, Valencia, Spain
| | - Desamparados Escudero-García
- Servicio de Medicina Digestiva, Hospital Clinico Universitario de Valencia, Valencia, Spain
- Departamento de Medicina, University of Valencia, Valencia, Spain
| | - Elena Kosenko
- Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, Pushchino, Russia
| | - Vicente Belloch
- Universitats Neurorradiology Unit, Ascires Biomedical Group, Valencia, Spain
| | - Carmina Montoliu
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain.
- Department of Pathology, Faculty of Medicine, University of Valencia, Av Blasco Ibáñez, 15, 46010, Valencia, Spain.
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Huang CH, Yu TY, Tseng WEJ, Huang YT, Chang SH, Hsieh SY, Chien RN, Amodio P. Animal naming test is a simple and valid tool for detecting covert hepatic encephalopathy and predicting outcomes in Chinese-speaking regions: a preliminary study. Ann Med 2023; 55:2236013. [PMID: 37494454 PMCID: PMC10373624 DOI: 10.1080/07853890.2023.2236013] [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: 04/05/2023] [Revised: 06/19/2023] [Accepted: 07/09/2023] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND AND AIMS Hepatic encephalopathy (HE) implies high morbidity and mortality. The assessment of covert HE (CHE) [i.e. minimal HE (MHE) plus grade 1 HE] is often neglected in Taiwan. Therefore, the aim was to investigate the potential of the animal naming test (ANT1 and simplified ANT1 (S-ANT1)) for assessing CHE in Chinese-speaking regions, specifically Taiwan. METHODS A prospective cohort study was conducted, comprising 65 cirrhotic patients and 29 healthy controls (relatives of the patients). Patients were followed up every three months and censored after two years or until death. Hospitalization for overt HE (OHE) and mortality were considered. All subjects underwent ANT1, psychometric HE score (PHES), and mini-mental state examination (MMSE). The patients underwent an electroencephalogram (EEG) to detect slowing indicative of MHE. Cut-off values for ANT1 and S-ANT1 were assessed by ROC analysis and Youden's index, considering CHE as a reference. The prognostic values for OHE and OHE-free survival were assessed. RESULTS Preliminary analysis confirmed that PHES ≤-4 is a good discriminant point for abnormal results. CHE was found in 29 patients: 9 had MHE (PHES ≤ -4 or altered EEG) and 20 had grade 1 HE. ANT1 and S-ANT1 were found to have diagnostic values for CHE: AUC = 0.807, 0.786; cut off: 18 and 19, respectively. ANT1 and S-ANT1 were found to have prognostic value for OHE, number of hospitalization episodes for OHE, and OHE recurrence-free survival. CONCLUSIONS ANT1 shows promise as a tool for CHE detection, quantification, and follow-up in Taiwan and other Chinese-speaking regions.Key messagesThe animal naming test (ANT1) is a simple and valid semantic fluency test that can be easily performed in outpatient or bedside settings in one minute and can also be used as a tool for covert hepatic encephalopathy (CHE) detection, quantification, and follow-up in Taiwan, other Chinese-speaking regions, and many other countries.The diagnostic value of ANT1 and S-ANT1 for CHE were found to be significant, with area under the receiver operating characteristic curve (AUROC) values of 0.807 and 0.786 respectively, and cut-off scores of 18 and 19.ANT1 and S-ANT1 have prognostic value for the first breakthrough of overt hepatic encephalopathy (OHE), number of hospitalization episodes for OHE, and OHE recurrence-free survival, independent of the MELD score.
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Affiliation(s)
- Chien-Hao Huang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Tung-Yang Yu
- College of Medicine, Chang-Gung University, Taoyuan, Taiwan
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Wei-En Johnny Tseng
- College of Medicine, Chang-Gung University, Taoyuan, Taiwan
- Section of Epilepsy, Department of Neurology, Chang Gung Memorial Hospital at Linkou Medical Center and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yu-Tung Huang
- Center for Big Data Analytics and Statistics, Department of Medical Research and Development, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Graduate Institute of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Shang-Hung Chang
- College of Medicine, Chang-Gung University, Taoyuan, Taiwan
- Graduate Institute of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan
- Cardiovascular Division, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
| | - Sen-Yung Hsieh
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Piero Amodio
- Department of Medicine, University of Padova, Padova, Italy
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Gilbert MC, Setayesh T, Wan YJY. The contributions of bacteria metabolites to the development of hepatic encephalopathy. LIVER RESEARCH 2023; 7:296-303. [PMID: 38221945 PMCID: PMC10786625 DOI: 10.1016/j.livres.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Over 20% of mortality during acute liver failure is associated with the development of hepatic encephalopathy (HE). Thus, HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma. HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels. Thus, the brain is exposed to intestinal-derived toxic substances. Moreover, the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation. This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE. Together, the significance of the gut-liver-brain axis in human health warrants attention. This review paper focuses on the roles of bacteria metabolites, mainly ammonia and bile acids (BAs) as well as BA receptors in HE. The literature search conducted for this review included searches for phrases such as BA receptors, BAs, ammonia, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy. PubMed, as well as Google Scholar, was the search engines used to find relevant publications.
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Affiliation(s)
- Miranda Claire Gilbert
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
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12
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Swansson WD, Anderson BM, Yeoh SW, Lewis DJ. Management of minimal and overt hepatic encephalopathy with branched-chain amino acids: a review of the evidence. Eur J Gastroenterol Hepatol 2023; 35:812-821. [PMID: 37395232 DOI: 10.1097/meg.0000000000002595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Hepatic encephalopathy (HE) is a challenging complication of liver disease that is associated with substantial morbidity and mortality. Branched-chain amino acid (BCAA) supplementation in the management of HE is a debated topic. This narrative review aims to provide an up-to-date review of the topic and includes studies featuring patients with hepatocellular carcinoma. A review of the literature was performed using the online databases MEDLINE and EMBASE for studies between 2002 and December 2022. Keywords 'branched-chain amino acids', 'liver cirrhosis' and 'hepatic encephalopathy' were used. Studies were assessed for inclusion and exclusion criteria. Of 1045 citations, 8 studies met the inclusion criteria. The main outcomes reported for HE was changed in minimal HE (MHE) (n = 4) and/or incidence of overt HE (OHE) (n = 7). Two of the 4 studies reporting on MHE had improvement in psychometric testing in the BCAA group, but there was no change in the incidence of OHE in any of the 7 papers in the BCAA group. There were few adverse effects of BCAA supplementation. This review found weak evidence for BCAA supplementation for MHE, and no evidence for BCAAs for OHE. However, given the relative paucity and methodological heterogeneity of the current research, there is scope for future studies to examine the effects of varying timing, dosage, and frequency of BCAAs on outcomes such as HE. Importantly, research is also needed to examine BCAAs in conjunction with standard therapies for HE such as rifaximin and/or lactulose.
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Affiliation(s)
| | | | - Sern Wei Yeoh
- Melbourne Medical School, The University of Melbourne
- Department of Gastroenterology, Northern Health, Melbourne, VIC, Australia
| | - Diana J Lewis
- Melbourne Medical School, The University of Melbourne
- Department of Gastroenterology, Northern Health, Melbourne, VIC, Australia
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13
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Santos RPC, Toscano ECDB, Rachid MA. Anti-inflammatory strategies for hepatic encephalopathy: preclinical studies. ARQUIVOS DE NEURO-PSIQUIATRIA 2023. [PMID: 37487550 PMCID: PMC10371400 DOI: 10.1055/s-0043-1767819] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Hepatic encephalopathy (HE) is a potentially reversible neuropsychiatric syndrome. Often, HE causes cognitive and motor dysfunctions due to an acute or chronic insufficiency of the liver or a shunting between the hepatic portal vein and systemic vasculature. Liver damage induces peripheral changes, such as in the metabolism and peripheral inflammatory responses that trigger exacerbated neuroinflammation. In experimental models, anti-inflammatory strategies have demonstrated neuroprotective effects, leading to a reduction in HE-related cognitive and motor impairments. In this scenario, a growing body of evidence has shown that peripheral and central nervous system inflammation are promising preclinical targets. In this review, we performed an overview of FDA-approved drugs and natural compounds which are used in the treatment of other neurological and nonneurological diseases that have played a neuroprotective role in experimental HE, at least in part, through anti-inflammatory mechanisms. Despite the exciting results from animal models, the available data should be critically interpreted, highlighting the importance of translating the findings for clinical essays.
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Affiliation(s)
- Rafaela Pinto Coelho Santos
- Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Patologia Geral, Laboratório de Patologia Celular e Molecular, Belo Horizonte MG, Brazil
| | - Eliana Cristina de Brito Toscano
- Universidade Federal de Juiz de Fora, Faculdade de Medicina, Departamento de Patologia, Laboratório Integrado de Pesquisa em Patologia, Juiz de Fora MG, Brazil
- Universidade Federal de Juiz e Fora, Faculdade de Medicina, Programa de Pós-Graduação em Saúde, Juiz de Fora MG, Brazil
| | - Milene Alvarenga Rachid
- Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Patologia Geral, Laboratório de Patologia Celular e Molecular, Belo Horizonte MG, Brazil
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14
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Zacharias HD, Kamel F, Tan J, Kimer N, Gluud LL, Morgan MY. Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2023; 7:CD011585. [PMID: 37467180 PMCID: PMC10360160 DOI: 10.1002/14651858.cd011585.pub2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/21/2023]
Abstract
BACKGROUND Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a key role in its development. Rifaximin is a non-absorbable antibiotic that inhibits urease-producing bacteria and reduces absorption of dietary and bacterial ammonia. OBJECTIVES To evaluate the beneficial and harmful effects of rifaximin versus placebo, no intervention, or non-absorbable disaccharides for: (i) the prevention of hepatic encephalopathy, and (ii) the treatment of minimal and overt hepatic encephalopathy, in people with cirrhosis, both when used alone and when combined with a non-absorbable disaccharide. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Clinical Trials Register, CENTRAL, MEDLINE, Embase, three other databases, the reference lists of identified papers, and relevant conference proceedings. We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials. Searches were performed to January 2023. SELECTION CRITERIA We included randomised clinical trials assessing prevention or treatment of hepatic encephalopathy with rifaximin alone, or with a non-absorbable disaccharide, versus placebo/no intervention, or a non-absorbable disaccharide alone. DATA COLLECTION AND ANALYSIS Six authors independently searched for studies, extracted data, and validated findings. We assessed the design, bias risk, and participant/intervention characteristics of the included studies. We assessed mortality, serious adverse events, health-related quality of life, hepatic encephalopathy, non-serious adverse events, blood ammonia, Number Connection Test-A, and length of hospital stay. MAIN RESULTS We included 41 trials involving 4545 people with, or at risk for, developing hepatic encephalopathy. We excluded 89 trials and identified 13 ongoing studies. Some trials involved participants with more than one type of hepatic encephalopathy or more than one treatment comparison. Hepatic encephalopathy was classed as acute (13 trials), chronic (7 trials), or minimal (8 trials), or else participants were considered at risk for its development (13 trials). The control groups received placebo (12 trials), no/standard treatment (1 trial), or a non-absorbable disaccharide (14 trials). Eighteen trials assessed rifaximin plus a non-absorbable disaccharide versus a non-absorbable disaccharide alone. We classified 11 trials as at high risk of overall bias for mortality and 28 for non-mortality outcomes, mainly due to lack of blinding, incomplete outcome data, and selective reporting. Compared to placebo/no intervention, rifaximin likely has no overall effect on mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.50 to 1.38; P = 48, I2 = 0%; 13 trials, 1007 participants; moderate-certainty evidence), and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.99, 95% CI 0.49 to 1.97; P = 0.97, I2 = 0%; 10 trials, 786 participants; low-certainty evidence). However, there is likely a reduction in the overall risk of mortality when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.69, 95% CI 0.55 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) = 22; P = 0.001, I2 = 0%; 14 trials, 1946 participants; moderate-certainty evidence). There is likely no effect on the overall risk of serious adverse events when comparing rifaximin to placebo/no intervention (RR 1.05, 95% CI 0.83 to 1.32; P = 68, I2 = 0%; 9 trials, 801 participants; moderate-certainty evidence) and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.97, 95% CI 0.66 to 1.40; P = 85, I2 = 0%; 8 trials, 681 participants; low-certainty evidence). However, there was very low-certainty evidence that use of rifaximin plus a non-absorbable disaccharide may be associated with a lower risk of serious adverse events than use of a non-absorbable disaccharide alone (RR 0.66, 95% CI 0.45 to 0.98; P = 0.04, I2 = 60%; 7 trials, 1076 participants). Rifaximin likely results in an overall effect on health-related quality of life when compared to placebo/no intervention (mean difference (MD) -1.43, 95% CI -2.87 to 0.02; P = 0.05, I2 = 81%; 4 trials, 214 participants; moderate-certainty evidence), and may benefit health-related quality of life in people with minimal hepatic encephalopathy (MD -2.07, 95% CI -2.79 to -1.35; P < 0.001, I2 = 0%; 3 trials, 176 participants). The overall effect on health-related quality of life when comparing rifaximin to non-absorbable disaccharides is very uncertain (MD -0.33, 95% CI -1.65 to 0.98; P = 0.62, I2 = 0%; 2 trials, 249 participants; very low-certainty evidence). None of the combined rifaximin/non-absorbable disaccharide trials reported on this outcome. There is likely an overall beneficial effect on hepatic encephalopathy when comparing rifaximin to placebo/no intervention (RR 0.56, 95% CI 0.42 to 0.77; NNTB = 5; P < 0.001, I2 = 68%; 13 trials, 1009 participants; moderate-certainty evidence). This effect may be more marked in people with minimal hepatic encephalopathy (RR 0.40, 95% CI 0.31 to 0.52; NNTB = 3; P < 0.001, I2 = 10%; 6 trials, 364 participants) and in prevention trials (RR 0.71, 95% CI 0.56 to 0.91; NNTB = 10; P = 0.007, I2 = 36%; 4 trials, 474 participants). There may be little overall effect on hepatic encephalopathy when comparing rifaximin to non-absorbable disaccharides (RR 0.85, 95% CI 0.69 to 1.05; P = 0.13, I2 = 0%; 13 trials, 921 participants; low-certainty evidence). However, there may be an overall beneficial effect on hepatic encephalopathy when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.58, 95% CI 0.48 to 0.71; NNTB = 5; P < 0.001, I2 = 62%; 17 trials, 2332 participants; low-certainty evidence). AUTHORS' CONCLUSIONS Compared to placebo/no intervention, rifaximin likely improves health-related quality of life in people with minimal hepatic encephalopathy, and may improve hepatic encephalopathy, particularly in populations with minimal hepatic encephalopathy and when it is used for prevention. Rifaximin likely has no overall effect on mortality, serious adverse events, health-related quality of life, or hepatic encephalopathy compared to non-absorbable disaccharides. However, when used in combination with a non-absorbable disaccharide, it likely reduces overall mortality risk, the risk of serious adverse events, improves hepatic encephalopathy, reduces the length of hospital stay, and prevents the occurrence/recurrence of hepatic encephalopathy. The certainty of evidence for these outcomes is very low to moderate; further high-quality trials are needed.
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Affiliation(s)
- Harry D Zacharias
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Fady Kamel
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Jaclyn Tan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Nina Kimer
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Lise Lotte Gluud
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
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15
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Thornburg B. Hepatic Encephalopathy following Transjugular Intrahepatic Portosystemic Shunt Placement. Semin Intervent Radiol 2023; 40:262-268. [PMID: 37484451 PMCID: PMC10359131 DOI: 10.1055/s-0043-1769770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
Hepatic encephalopathy (HE) is a complex condition that arises as a complication of chronic liver disease and portosystemic shunting. Its pathophysiology involves several factors, including impaired ammonia metabolism, portosystemic shunting, sarcopenia, and systemic inflammation. The symptoms of HE can vary significantly, with manifestations ranging from subclinical signs to a comatose state. The West Haven classification system is most commonly used to grade the severity of HE. There is a broad differential for the presenting symptomatology of HE and other causes of altered mental status must be excluded during the workup. HE is a well-known complication of transjugular intrahepatic portosystemic shunt (TIPS) placement. Even though newer stent designs help reduce the risk of HE with smaller diameter shunts, it is essential that patients are counseled regarding this potential risk prior to the procedure. Once a diagnosis of HE has been confirmed, the mainstay of therapy is lactulose and rifaximin. In cases where a patient has received a TIPS placement and continues to experience refractory HE despite medical therapy, it may be necessary to consider shunt reduction or closure.
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Affiliation(s)
- Bartley Thornburg
- Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Chicago, Illinois
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16
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Hayakawa Y, Tamaki N, Nakanishi H, Kurosaki M, Tanaka Y, Inada K, Ishido S, Kirino S, Yamashita K, Nobusawa T, Matsumoto H, Kakegawa T, Higuchi M, Takaura K, Tanaka S, Maeyashiki C, Kaneko S, Yasui Y, Takahashi Y, Tsuchiya K, Okamoto R, Izumi N. Add-on Therapeutic Effects of Rifaximin on Treatment-resistant Hepatic Encephalopathy. Intern Med 2023; 62:973-978. [PMID: 36070941 PMCID: PMC10125807 DOI: 10.2169/internalmedicine.0212-22] [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] [Indexed: 11/06/2022] Open
Abstract
Objective Rifaximin is used to treat hepatic encephalopathy. However, whether or not rifaximin and lactulose combination therapy can enhance the treatment outcomes and reduce the hospitalization rate of patients with hepatic encephalopathy that are resistant to lactulose has yet to be determined. The present study investigated the hospitalization rate before and after rifaximin add-on therapy in patients resistant to lactulose. Methods A total of 36 patients who were resistant to lactulose with add-on rifaximin therapy were enrolled. Patients who were hospitalized and/or did not achieve normalization of ammonia levels under lactulose administration were defined as treatment-resistant. The primary outcome was the change in hospitalization rate due to hepatic encephalopathy at 24 weeks before and after rifaximin administration. Results Before rifaximin administration, 15 (41.6%) patients were hospitalized due to hepatic encephalopathy. After rifaximin administration, 8 (22.2%) patients were hospitalized due to hepatic encephalopathy. The hospitalization rates were significantly reduced after rifaximin administration (p=0.02). The median (interquartile range) ammonia levels upon rifaximin administration (baseline) and 8, 12, and 24 weeks after rifaximin administration were 124 (24-310) μg/dL, 78 (15-192) μg/dL, 67 (21-233) μg/dL, and 77 (28-200) μg/dL, respectively. Furthermore, the ammonia levels were significantly reduced by rifaximin add-on therapy (p=0.005, p=0.01, and p=0.01). Conclusion The addition of rifaximin to lactulose treatment in treatment-resistant patients decreases the hospitalization rate among patients with hepatic encephalopathy and may be used as an add-on treatment.
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Affiliation(s)
- Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Yuki Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Shun Ishido
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
| | - Tsubasa Nobusawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Hiroaki Matsumoto
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Tatsuya Kakegawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
| | - Shohei Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Japan
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17
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Old and New Precipitants in Hepatic Encephalopathy: A New Look at a Field in Continuous Evolution. J Clin Med 2023; 12:jcm12031187. [PMID: 36769836 PMCID: PMC9917479 DOI: 10.3390/jcm12031187] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Hepatic encephalopathy (HE) is a common complication in patients with advanced liver disease. It is a brain dysfunction characterized by neurological and psychiatric symptoms that significantly affects quality of life, morbidity and mortality of patients. HE has various precipitants that can potentially promote its onset, alone or in combination. Among the historically well-known precipitants, such as infections, gastrointestinal bleeding, dehydration, electrolyte disorders and constipation, recent studies have highlighted the role of malnutrition and portosystemic shunts as new precipitating factors of HE. The identification, management and correction of these factors are fundamental for effective HE treatment, in addition to pharmacological therapy with non-absorbable disaccharides and/or antibiotics.
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18
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Stoll AM, Guido M, Pence A, Gentene AJ. Lack of Access to Rifaximin Upon Hospital Discharge Is Frequent and Results in Increased Hospitalizations for Hepatic Encephalopathy. Ann Pharmacother 2023; 57:133-140. [PMID: 35658580 DOI: 10.1177/10600280221100537] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) is a complication of cirrhosis. Rifaximin, added to lactulose, effectively maintains remission and reduces hospitalizations from HE compared with lactulose alone. Although the clinical evidence supports the use of rifaximin, concerns remain regarding the financial implications and subsequent impact on medication access and outcomes. OBJECTIVE The goal of this study was to determine whether medication access to rifaximin at hospital discharge reduces readmission and office visits related to HE. METHODS A retrospective study was conducted in compliance with local institutional review board including cirrhotic patients discharged with a rifaximin prescription for HE. Patients were stratified into 2 groups: those able to obtain rifaximin and those unable to obtain rifaximin upon discharge. The primary outcome was to evaluate the rate of HE recurrence in each group as defined as a composite of readmission or office visit for acute HE within 12 months of discharge. RESULTS Access to rifaximin significantly reduced the risk of hospital admission and office visit for acute HE over 12 months. A hospitalization or office visit occurred in 24.5% of patients in the medication access group compared with 50% in the group without medication access. Only 58% of patients had access to rifaximin at discharge. CONCLUSION AND RELEVANCE Rifaximin use was associated with significantly reduced risk of hospitalization and office visits for HE. At discharge, 42% of patients did not have access to rifaximin regardless of being prescribed the medication, identifying that copay is a significant barrier in allowing patients to have access to rifaximin.
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Affiliation(s)
- Ann Marie Stoll
- Internal Medicine, Department of Pharmacy Services, University of Cincinnati Medical Center, UC Health, Cincinnati, OH, USA
| | - Maria Guido
- Internal Medicine, Department of Pharmacy Services, University of Cincinnati Medical Center, UC Health, Cincinnati, OH, USA.,Division of Pharmacy Practice and Administration, University of Cincinnati James L. Winkle College of Pharmacy, Cincinnati, OH, USA
| | - Alicia Pence
- Specialty Pharmacy, Department of Pharmacy Services, University of Cincinnati Specialty Pharmacy, UC Health, Cincinnati, OH, USA
| | - Anthony J Gentene
- Internal Medicine, Department of Pharmacy Services, University of Cincinnati Medical Center, UC Health, Cincinnati, OH, USA.,Division of Pharmacy Practice and Administration, University of Cincinnati James L. Winkle College of Pharmacy, Cincinnati, OH, USA
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19
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Abstract
Hepatic encephalopathy (HE) is brain dysfunction secondary to liver insufficiency or portosystemic shunting. HE is a major burden on patients and caregivers, impairs quality of life and is associated with higher mortality. Overt HE is a clinical diagnosis while Covert HE, needs specialized diagnostic strategies. Mainstay of treatment of HE is nonabsorbable disaccharides such as lactulose as well as rifaximin; however, investigational therapies are discussed in this review. Better tools are needed to prognosticate which patients will go on to develop HE but microbiome and metabolomic-driven strategies are promising. Here we review methods to prevent the HE development and admissions.
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20
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Kwong AJ, Zahr NM. Serum biomarkers of liver fibrosis identify globus pallidus vulnerability. Neuroimage Clin 2023; 37:103333. [PMID: 36868044 PMCID: PMC9996367 DOI: 10.1016/j.nicl.2023.103333] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 01/12/2023] [Accepted: 01/19/2023] [Indexed: 01/28/2023]
Abstract
The CNS manifestation of chronic liver disease can include magnetic resonance (MR) signal hyperintensities in basal ganglia structures. Here, relations between liver (serum-derived fibrosis scores) and brain (regional T1-weighted signal intensities and volumes) integrity were evaluated in a sample of 457 individuals including those with alcohol use disorders (AUD), people living with human immunodeficiency virus (HIV), those comorbid for AUD and HIV, and healthy controls. Liver fibrosis was identified from cutoff scores as follows: aspartate aminotransferase to platelet ratio index (APRI) > 0.7 in 9.4% (n = 43) of the cohort; fibrosis score (FIB4) > 1.5 in 28.0% (n = 128) of the cohort; and non-alcoholic fatty liver disease fibrosis score (NFS) > -1.4 in 30.2% (n = 138) of the cohort. Presence of serum-derived liver fibrosis was associated with high signal intensities selective to basal ganglia (i.e., caudate, putamen, and pallidum) structures. High signal intensities in the pallidum, however, explained a significant portion of the variance in APRI (25.0%) and FIB4 (23.6%) cutoff scores. Further, among the regions evaluated, only the globus pallidus showed a correlation between greater signal intensity and smaller volume (r = -0.44, p <.0001). Finally, higher pallidal signal intensity correlated worse ataxia (eyes open ρ = -0.23, p =.0002; eyes closed ρ = -0.21, p =.0005). This study suggests that clinically relevant serum biomarkers of liver fibrosis such as the APRI may identify individuals vulnerable to globus pallidus pathology and contribute to problems with postural balance.
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Affiliation(s)
- Allison J Kwong
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, School of Medicine, Redwood City, CA 94063, USA
| | - Natalie M Zahr
- Department of Psychiatry & Behavioral Sciences, Stanford University, School of Medicine, 401 Quarry Rd. Stanford, CA 94305, USA; Neuroscience Program, SRI International, Menlo Park, CA 94025, USA.
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21
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Huang L, Yu Q, Peng H, Zhen Z. Alterations of gut microbiome and effects of probiotic therapy in patients with liver cirrhosis: A systematic review and meta-analysis. Medicine (Baltimore) 2022; 101:e32335. [PMID: 36595801 PMCID: PMC9794299 DOI: 10.1097/md.0000000000032335] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Alterations in the gut microbiome usually occur in liver cirrhosis. Gut microbiome dysregulation damages the liver and accelerates the development of liver fibrosis. Probiotic treatment has gradually become a major method for improving the prognosis of liver cirrhosis and reducing its complications. However, alterations in the gut microbiome have revealed different results, and the therapeutic effects of various probiotics are inconsistent. METHODS We searched the PubMed, Medline, EMBASE, ScienceDirect, and Cochrane databases up to August 2022 and conducted a systematic review and meta-analysis of 17 relevant studies. RESULTS The counts of Enterobacter (standardized mean difference [SMD] -1.79, 95% confidence interval [CI]: -3.08 to -0.49) and Enterococcus (SMD -1.41, 95% CI: -2.26 to -0.55) increased significantly in patients with cirrhosis, while the counts of Lactobacillus (SMD 0.63, 95% CI: 0.12-1.15) and Bifidobacterium (SMD 0.44, 95% CI: 0.12-0.77) decreased significantly. Blood ammonia (weighted mean difference [WMD] 14.61, 95% CI: 7.84-21.37) and the incidence of hepatic encephalopathy (WMD 0.40, 95% CI: 0.27-0.61) were significantly decreased in the probiotic group. As for mortality (MD 0.75, 95% CI: 0.48-1.16) and the incidence of spontaneous bacterial peritonitis (WMD -0.02, 95% CI: -0.07 to 0.03), no significant differences were found between the probiotic and placebo groups. CONCLUSION In summary, the gut microbiome in cirrhosis manifests as decreased counts of Lactobacillus and Bifidobacterium and increased counts of Enterobacter and Enterococcus. Targeted supplementation of probiotics in cirrhosis, including Lactobacillus combined with Bifidobacterium or Bifidobacterium alone, can reduce blood ammonia and the incidence of hepatic encephalopathy. The effect is similar to that of lactulose, but it has no obvious effect on mortality and spontaneous bacterial peritonitis.
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Affiliation(s)
- Long Huang
- Department of No. 1 Surgery, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
- * Correspondence: Long Huang, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, No. 117 Meishan Road, Hefei, Anhui Province 230031, China (e-mail: )
| | - Qingsheng Yu
- Department of No. 1 Surgery, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
| | - Hui Peng
- Department of No. 1 Surgery, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
| | - Zhou Zhen
- Department of Surgery, The Second Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
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Zhang P, Zhou L, Chen L, Zhang Z, Han R, Guo G, Zhou H. Electroencephalography Signatures for Hepatic Encephalopathy in Cirrhosis Patients Treated with Proton Pump Inhibitors: An Exploratory Pilot Study. Biomedicines 2022; 10:biomedicines10123040. [PMID: 36551796 PMCID: PMC9776374 DOI: 10.3390/biomedicines10123040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/15/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022] Open
Abstract
(1) Background: Hepatic encephalopathy (HE) is a common complication in cirrhosis patients, and recently, clinical evidence indicates that a higher risk of HE is associated with the usage of proton pump inhibitors. However, the cortical mechanism underlying this neurological disorder of HE remains unknown. (2) Methods: We review the medical recordings of 260 patients diagnosed with liver cirrhosis between January 2021 and March 2022 in one tertiary hospital. Logistic regression analyses were performed to identify the risk factor of HE development. To examine the relationship between cortical dynamics and the administration of proton pump inhibitors, resting-state electroencephalograms (EEGs) were conducted in cirrhosis patients who were treated with proton pump inhibitors. (3) Results: About 28.5% (74 out of 260) of participants developed secondary HE in this study. The logistics regression model indicated that multiple risk factors were associated with the incidence of secondary HE, including proton pump inhibitors usage, white blood cell and neutrophil counts, hemoglobin, prothrombin time activity, and blood urea nitrogen. A total of twelve cirrhosis patients who were scheduled to use proton pump inhibitors consented to performing electroencephalogram recordings upon admission, and eight of twelve participants were diagnosed with HE. Spectral analysis revealed that the decrease in alpha oscillation activities was potentially associated with the development of HE. (4) Conclusions: Our data support the susceptibility of secondary HE in cirrhosis patients treated by proton pump inhibitors. One potential cortical mechanism underlying the neurological disease is the suppression of alpha oscillations in the brain.
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Affiliation(s)
- Pan Zhang
- Department of Infectious Diseases, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Lizhi Zhou
- Department of Infectious Diseases, Third Xiangya Hospital, Central South University, Changsha 410013, China
- Department of Infectious Diseases, Xiangtan Central Hospital, Xiangtan 411100, China
| | - Li Chen
- Department of Pain, Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha 410013, China
| | - Zhen Zhang
- Department of Pain, Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha 410013, China
| | - Rui Han
- Department of Pain, Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha 410013, China
| | - Gangwen Guo
- Department of Pain, Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha 410013, China
- Correspondence: (G.G.); (H.Z.)
| | - Haocheng Zhou
- Department of Pain, Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha 410013, China
- Hunan Key Laboratory of Brain Homeostasis, Central South University, Changsha 410013, China
- Correspondence: (G.G.); (H.Z.)
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Nutritional Support in Acute Liver Failure. Diseases 2022; 10:diseases10040108. [PMID: 36412602 PMCID: PMC9680263 DOI: 10.3390/diseases10040108] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/14/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022] Open
Abstract
Acute liver failure (ALF) presents with an acute abnormality of liver blood tests in an individual without underlying chronic liver disease. The clinical course leads to the development of coagulopathy and hepatic encephalopathy. The role of nutrition in its prevention and treatment remains uncertain. We aimed to review literature data on the concept of ALF and the role of nutrition in its treatment and prevention, considering the impact of gut microbiota dysbiosis and eubiosis. We conducted a review of the literature on the main medical databases using the following keywords and acronyms and their associations: liver failure, nutrition, branched-chain amino acids, gut microbiota, dysbiosis, and probiotics. Upon their arrival at the emergency department, an early, accurate nutritional assessment is crucial for individuals with ALF. Branched-chain amino acids (BCAAs), stable euglycemia maintenance, and moderate caloric support are crucial for this subset of patients. An excessive protein load must be avoided because it worsens hepatic encephalopathy. Preclinical evidence supports future probiotics use for ALF treatment/prevention. Nutritional support and treatment for ALF are crucial steps against patient morbidity and mortality. BCAAs and euglycemia remain the mainstay of nutritional treatment of ALF. Gut dysbiosis re-modulation has an emerging and natural-history changing impact on ALF.
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Yokoyama K, Fukuda H, Yamauchi R, Higashi M, Miyayama T, Higashi T, Uchida Y, Shibata K, Tsuchiya N, Fukunaga A, Umeda K, Takata K, Tanaka T, Shakado S, Sakisaka S, Hirai F. Long-Term Effects of Rifaximin on Patients with Hepatic Encephalopathy: Its Possible Effects on the Improvement in the Blood Ammonia Concentration Levels, Hepatic Spare Ability and Refractory Ascites. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58091276. [PMID: 36143954 PMCID: PMC9501622 DOI: 10.3390/medicina58091276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/09/2022] [Accepted: 09/11/2022] [Indexed: 11/20/2022]
Abstract
Background and Objectives: To investigate the long-term efficacy of rifaximin (RFX) for hyperammonemia and efficacy for refractory ascites in patients with cirrhosis. Materials and Methods: We enrolled 112 patients with liver cirrhosis who were orally administered RFX in this study. Changes in the clinical data of patients were evaluated up to 36 months after RFX administration. The primary endpoint was a change in blood ammonia levels. Secondary endpoints included changes in clinical symptoms, Child−Pugh (CP) score, number of hospitalizations, degree of refractory ascites, adverse events, and the relationship between RFX administration and the renin-angiotensin-aldosterone system. Results: An improved rate of overt hepatic encephalopathy (HE) of 82.7% was observed 3 months after RFX administration, which significantly induced a progressive decrease in blood ammonia concentration and an improved CP score up to 36 months. No serious RFX treatment-related adverse events were observed. 36.5% in patients after RFX administration improved refractory ascites. After RFX administration, patients with satisfactory control of hepatic ascites without addition of diuretic had lower renin concentration than those with poor control (p < 0.01). At less than 41 pg/mL renin concentration, the control of refractory ascites was significantly satisfactory (p < 0.0001). Conclusions: RFX reduced blood ammonia concentration and improved hepatic spare ability and the quality of life of patients with long-term HE to up to 36 months. Our study revealed the effects of RFX against refractory ascites, suggesting that renin concentration may be a predictive marker for assessing ascites control.
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Affiliation(s)
- Keiji Yokoyama
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
- Correspondence: ; Tel.: +81-92-801-1011 (ext. 3355)
| | - Hiromi Fukuda
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Ryo Yamauchi
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Masashi Higashi
- Higashi Hospital, 593-1 Hirotsu, Yositomi-machi, Chikujo-gun 871-0811, Fukuoka, Japan
| | - Takashi Miyayama
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Tomotaka Higashi
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Yotaro Uchida
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Kumiko Shibata
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Naoaki Tsuchiya
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Atsushi Fukunaga
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Kaoru Umeda
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Kazuhide Takata
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Takashi Tanaka
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Satoshi Shakado
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Shotaro Sakisaka
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Fumihito Hirai
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
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Hepatik Ensefalopati Tip C Hastalarında Tetikleyici Faktörler ve Kliniko-Endoskopik Çalışma. JOURNAL OF CONTEMPORARY MEDICINE 2022. [DOI: 10.16899/jcm.979964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Introduction: Hepatic encephalopathy (HE) is a decline in brain function as a result of severe liver disease and its inadequacy to remove toxins from the body. It is characterized by personality changes, intellectual impairment, and loss of consciousness. This study was conducted to determine the precipitating factors and endoscopic features of hepatic encephalopathy in patients with liver cirrhosis and evaluate the associated clinical features admitted in a tertiary hospital in Central India.
Materials and Methods: This hospital-based descriptive cross-sectional study was conducted from November 2016 to October 2018 on 102 patients with hepatic encephalopathy type C, aged above 18. All patients were carefully examined, relevant investigations performed, and data collected through pre-designed proforma. They were sent for statistical analysis where categorical outcomes were compared between study groups using the Chi-square test /Fisher's Exact test.
Results: The prevalence of HE was 19.6% in our study. In this study, we observed that constipation (26.5%), electrolyte imbalance (21.6%), renal failure (18.6%), and upper GI bleeding (18.6%) be among the leading precipitants for HE. Besides liver failure, the associated abnormalities in various factors like coagulation abnormalities, renal derangement, and changes in serum sodium levels can lead to the progression of HE to higher grades.
Conclusion: It is essential to identify the different factors like constipation, electrolyte imbalance, renal failure, and upper GI bleeding early in the course of cirrhosis to help prevent the development of HE.
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Manzhalii E, Moyseyenko V, Kondratiuk V, Molochek N, Falalyeyeva T, Kobyliak N. Effect of a specific Escherichia coli Nissle 1917 strain on minimal/mild hepatic encephalopathy treatment. World J Hepatol 2022; 14:634-646. [PMID: 35582294 PMCID: PMC9055191 DOI: 10.4254/wjh.v14.i3.634] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 02/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) can be considered a result of dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by "gut-centric" therapies, such as the administration of nonabsorbable disaccharides, nonabsorbable antibiotics, probiotics and prebiotics. AIM To assess the short-term efficacy and safety of the probiotic Escherichia coli Nissle (EcN) 1917 strain compared to lactulose and rifaximin in patients with minimal/mild HE. METHODS From January 2017 to March 2020, a total of 45 patients with HE were enrolled in this prospective, single-centre, open-label, randomized study. Participants were randomly assigned at a ratio of 1:1:1 to one of the treatment groups: The EcN group (n = 15), lactulose group (n = 15) or rifaximin group (n = 15) for a 1 mo intervention period. The main primary outcomes of the study were changes in serum ammonia and Stroop test score. The secondary outcomes were markers of a chronic systemic inflammatory response (ІL-6, ІL-8, and IFN-γ) and bacteriology of the stool flora evaluated by specialized nonculture techniques after a 1 mo intervention period. RESULTS Patients who were given rifaximin or EcN showed a more significant reduction in serum ammonia and normalization of Bifidobacteria and Lactobacilli abundance compared to the lactulose group. However, the most pronounced restoration of the symbiotic microflora was associated with EcN administration and characterized by the absence of E. coli with altered properties and pathogenic enterobacteria in patient faeces. In the primary outcome analysis, improvements in the Stroop test parameters in all intervention groups were observed. Moreover, EcN-treated patients performed 15% faster on the Stroop test than the lactulose group patients (P = 0.017). Both EcN and rifaximin produced similar significant reductions in the proinflammatory cytokines INF-γ, IL-6 and IL-8. EcN was more efficient than lactulose in reducing proinflammatory cytokine levels. CONCLUSION The use of the probiotic EcN strain was safe and quite efficient for HE treatment. The probiotic reduced the ammonia content and the level of serum proinflammatory cytokines, normalized the gut microbiota composition and improved the cognitive function of patients with HE. The application of the EcN strain was more effective than lactulose treatment.
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Affiliation(s)
- Elina Manzhalii
- Department of Propedeutics of Internal Medicine, Bogomolets National Medical University, Kyiv 01601, Ukraine.
| | - Valentyna Moyseyenko
- Department of Propedeutics of Internal Medicine, Bogomolets National Medical University, Kyiv 01601, Ukraine
| | - Vitalii Kondratiuk
- Department of Propedeutics of Internal Medicine, Bogomolets National Medical University, Kyiv 01601, Ukraine
| | - Nataliia Molochek
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
- Department of Pediatrics, Bogomolets National Medical University, Kyiv 01601, Ukraine
| | - Tetyana Falalyeyeva
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
- Department of Scientific, Medical Laboratory CSD, Kyiv 01004, Ukraine
| | - Nazarii Kobyliak
- Department of Endocrinology, Bogomolets National Medical University, Kyiv 01601, Ukraine
- Department of Scientific, Medical Laboratory CSD, Kyiv 01004, Ukraine.
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Tasnim S, Hazam R, Dave D, Yousuf H, Khan M, Patel M. Reversible Decerebrate Posture in Hepatic Encephalopathy: Case Report and Literature Review. Cureus 2022; 14:e21960. [PMID: 35282560 PMCID: PMC8904031 DOI: 10.7759/cureus.21960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2022] [Indexed: 11/05/2022] Open
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Is NMDA-Receptor-Mediated Oxidative Stress in Mitochondria of Peripheral Tissues the Essential Factor in the Pathogenesis of Hepatic Encephalopathy? J Clin Med 2022; 11:jcm11030827. [PMID: 35160278 PMCID: PMC8836479 DOI: 10.3390/jcm11030827] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/01/2022] [Accepted: 02/03/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome of increased ammonia-mediated brain dysfunction caused by impaired hepatic detoxification or when the blood bypasses the liver. Ammonia-activated signal transduction pathways of hyperactivated NMDA receptors (NMDAR) are shown to trigger a cascade of pathological reactions in the brain, leading to oxidative stress. NMDARs outside the brain are widely distributed in peripheral tissues, including the liver, heart, pancreas, and erythrocytes. To determine the contribution of these receptors to ammonia-induced oxidative stress in peripheral tissues, it is relevant to investigate if there are any ammonia-related changes in antioxidant enzymes and free radical formation and whether blockade of NMDARs prevents these changes. Methods: Hyperammonemia was induced in rats by ammonium acetate injection. Oxidative stress was measured as changes in antioxidant enzyme activities and O2•− and H2O2 production by mitochondria isolated from the tissues and cells mentioned above. The effects of the NMDAR antagonist MK-801 on oxidative stress markers and on tissue ammonia levels were evaluated. Results: Increased ammonia levels in erythrocytes and mitochondria isolated from the liver, pancreas, and heart of hyperammonemic rats are shown to cause tissue-specific oxidative stress, which is prevented completely (or partially in erythrocyte) by MK-801. Conclusions: These results support the view that the pathogenesis of HE is multifactorial and that ammonia-induced multiorgan oxidative stress-mediated by activation of NMDAR is an integral part of the disease and, therefore, the toxic effects of ammonia in НЕ may be more global than initially expected.
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Abdel Moneim M, Abdelaziz DH, Ibrahim Nagy Y, Abdel Baki A, Attia AS, Sabry N. Rifaximin microbial resistance and its efficacy and safety as a secondary prophylaxis of hepatic encephalopathy in patients with hepatitis C virus-related cirrhosis. Int J Clin Pract 2021; 75:e14807. [PMID: 34487412 DOI: 10.1111/ijcp.14807] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/14/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIM Rifaximin is an oral antibiotic with promising efficacy in the reduction of hepatic encephalopathy (HE) recurrence. Development of microbial resistance to rifaximin is not studied yet in HE. The study aim was to assess the microbial resistance, safety and efficacy of rifaximin as secondary prophylaxis of HE. METHOD In this open-label parallel, prospective interventional study, 100 patients were randomly allocated either to receive 400 mg rifaximin 3 times/d plus 30-45 mL lactulose 3 times/d (intervention group) or to receive the standard of care only which is lactulose alone (control group) for 6 months. The primary outcome of the study was the difference between minimum inhibitory concentration (MIC) of rifaximin among the two studied groups at the end of treatment. The secondary outcomes included the time to first episode of HE, time to first hospitalisation, and patient's survival. RESULTS The MIC did not differ significantly after treatment exposure compared with baseline either between groups or within the same group. The time to new episode of HE was 18.84 ± 6.49 weeks (mean ± SD) in the intervention group and was significantly longer (P = .002) than that in the control group 14 ± 7.52 weeks. Moreover, only 23 (46%) patients developed overt HE in the intervention group compared with 35 patients (70%) in the control group (P = .005). Also, there was an observed 32% reduction in the risk of hospitalisation in intervention group compared with control group. CONCLUSION Rifaximin succeeded to maintain remission from new episodes of HE in hepatitis C virus cirrhotic patients with limited potential for development of microbial resistance over the study period. ClinicalTrials.gov Identifier: NCT04736836.
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Affiliation(s)
- Mai Abdel Moneim
- Clinical Pharmacy Department, The National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Doaa H Abdelaziz
- Clinical Pharmacy Department, The National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
| | - Yosra Ibrahim Nagy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Amin Abdel Baki
- Hepatology, Gastroenterology and Infectious Diseases Department, The National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Ahmed S Attia
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nirmeen Sabry
- Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Yang H, Li X, Cao H, Cui Y, Luo Y, Liu J, Zhang Y. Using machine learning methods to predict hepatic encephalopathy in cirrhotic patients with unbalanced data. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2021; 211:106420. [PMID: 34555589 DOI: 10.1016/j.cmpb.2021.106420] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 09/11/2021] [Indexed: 06/13/2023]
Abstract
OBJECTIVE Hepatic encephalopathy (HE) is among the most common complications of cirrhosis. Data for cirrhosis with HE is typically unbalanced. Traditional statistical methods and machine learning algorithms thus cannot identify a few classes. In this paper, we use machine learning algorithms to construct a risk prediction model for liver cirrhosis complicated by HE to improve the efficiency of its prediction. METHOD We collected medical data from 1,256 patients with cirrhosis and performed preprocessing to extract 81 features from these irregular data. To predict HE in cirrhotic patients, we compared several classification methods: logistic regression, weighted random forest (WRF), SVM, and weighted SVM (WSVM). We also used an additional 722 patients with cirrhosis for external validation of the model. RESULTS The WRF, WSVM, and logistic regression models exhibited better recognition ability for patients with HE than traditional machine learning models (sensitivity> 0.70), but their ability to identify patients with uncomplicated HE was slightly lower (specificity approximately 85%). The comprehensive evaluation index of the traditional model was higher than those of other models (G-means> 0.80 and F-measure> 0.40). For the WRF, the G-means (0.82), F-measure (0.46), and AUC (0.82) were superior to those of the logistic regression and WSVM models, which means that it can better predict the incidence of HE in patients. CONCLUSION The WRF model is more suitable for the classification of unbalanced medical data and can be used to construct a risk prediction and evaluation system for liver cirrhosis complicated with HE. The probabilistic prediction models of WRF can help clinicians identify high-risk patients with HE.
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Affiliation(s)
- Hong Yang
- Department of Health Statistics, Shanxi Medical University, Taiyuan, China
| | - Xinxin Li
- Department of Health Statistics, Shanxi Medical University, Taiyuan, China
| | - Hongyan Cao
- Department of Health Statistics, Shanxi Medical University, Taiyuan, China
| | - Yuehua Cui
- Department of Statistics and Probability, Michigan State University, East Lansing, USA
| | - Yanhong Luo
- Department of Health Statistics, Shanxi Medical University, Taiyuan, China
| | - Jinchun Liu
- Department of Gastroenterology, the First Hospital of Shanxi Medical University, Taiyuan, China.
| | - Yanbo Zhang
- Department of Health Statistics, Shanxi Medical University, Taiyuan, China.
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Jeon SJ, Choi SS, Kim HY, Yu IK. Acute Acquired Metabolic Encephalopathy Based on Diffusion MRI. Korean J Radiol 2021; 22:2034-2051. [PMID: 34564957 PMCID: PMC8628163 DOI: 10.3348/kjr.2019.0303] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 11/02/2020] [Accepted: 11/20/2020] [Indexed: 11/22/2022] Open
Abstract
Metabolic encephalopathy is a critical condition that can be challenging to diagnose. Imaging provides early clues to confirm clinical suspicions and plays an important role in the diagnosis, assessment of the response to therapy, and prognosis prediction. Diffusion-weighted imaging is a sensitive technique used to evaluate metabolic encephalopathy at an early stage. Metabolic encephalopathies often involve the deep regions of the gray matter because they have high energy requirements and are susceptible to metabolic disturbances. Understanding the imaging patterns of various metabolic encephalopathies can help narrow the differential diagnosis and improve the prognosis of patients by initiating proper treatment regimen early.
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Affiliation(s)
- Se Jeong Jeon
- Department of Radiology, Wonkwang University Hospital, Iksan, Korea
| | - See Sung Choi
- Department of Radiology, Wonkwang University Hospital, Iksan, Korea
| | - Ha Yon Kim
- Department of Radiology, Eulji University Hospital, Deajeon, Korea
| | - In Kyu Yu
- Department of Radiology, Eulji University Hospital, Deajeon, Korea.
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Kim YK, Song J. Therapeutic Applications of Resveratrol in Hepatic Encephalopathy through Its Regulation of the Microbiota, Brain Edema, and Inflammation. J Clin Med 2021; 10:jcm10173819. [PMID: 34501267 PMCID: PMC8432232 DOI: 10.3390/jcm10173819] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic encephalopathy is a common complication in patients with liver cirrhosis and portosystemic shunting. Patients with hepatic encephalopathy present a variety of clinical features, including neuropsychiatric manifestations, cognitive dysfunction, impaired gut barrier function, hyperammonemia, and chronic neuroinflammation. These pathogeneses have been linked to various factors, including ammonia-induced oxidative stress, neuronal cell death, alterations in the gut microbiome, astrocyte swelling, and blood-brain barrier disruptions. Many researchers have focused on identifying novel therapeutics and prebiotics in the hope of improving the treatment of these conditions. Resveratrol is a natural polyphenic compound and is known to exert several pharmacological effects, including antioxidant, anti-inflammatory, and neuroprotective activities. Recent studies suggest that resveratrol contributes to improving the neuropathogenic effects of liver failure. Here, we review the current evidence describing resveratrol's effects in neuropathogenesis and its impact on the gut-liver axis relating to hepatic encephalopathy. We highlight the hypothesis that resveratrol exerts diverse effects in hepatic encephalopathy and suggest that these effects are likely mediated by changes to the gut microbiota, brain edema, and neuroinflammation.
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Affiliation(s)
- Young-Kook Kim
- Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Jeollanam-do, Korea;
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Jeollanam-do, Korea
- Correspondence: ; Tel.: +82-61-379-2706; Fax: +82-61-375-5834
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Hayward KL, Johnson AL, Mckillen BJ, Burke NT, Bansal V, Horsfall LU, Hartel G, Moser C, Powell EE, Valery PC. ICD-10-AM codes for cirrhosis and related complications: key performance considerations for population and healthcare studies. BMJ Open Gastroenterol 2021; 7:bmjgast-2020-000485. [PMID: 32943463 PMCID: PMC7500192 DOI: 10.1136/bmjgast-2020-000485] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 07/29/2020] [Accepted: 08/08/2020] [Indexed: 12/14/2022] Open
Abstract
Objective The utility of International Classification of Diseases (ICD) codes relies on the accuracy of clinical reporting and administrative coding, which may be influenced by country-specific codes and coding rules. This study explores the accuracy and limitations of the Australian Modification of the 10th revision of ICD (ICD-10-AM) to detect the presence of cirrhosis and a subset of key complications for the purpose of future large-scale epidemiological research and healthcare studies. Design/method ICD-10-AM codes in a random sample of 540 admitted patient encounters at a major Australian tertiary hospital were compared with data abstracted from patients’ medical records by four blinded clinicians. Accuracy of individual codes and grouped combinations was determined by calculating sensitivity, positive predictive value (PPV), negative predictive value and Cohen’s kappa coefficient (κ). Results The PPVs for ‘grouped cirrhosis’ codes (0.96), hepatocellular carcinoma (0.97) ascites (0.97) and ‘grouped varices’ (0.95) were good (κ all >0.60). However, codes under-detected the prevalence of cirrhosis, ascites and varices (sensitivity 81.4%, 61.9% and 61.3%, respectively). Overall accuracy was lower for spontaneous bacterial peritonitis (‘grouped’ PPV 0.75; κ 0.73) and the poorest for encephalopathy (‘grouped’ PPV 0.55; κ 0.21). To optimise detection of cirrhosis-related encounters, an ICD-10-AM code algorithm was constructed and validated in an independent cohort of 116 patients with known cirrhosis. Conclusion Multiple ICD-10-AM codes should be considered when using administrative databases to study the burden of cirrhosis and its complications in Australia, to avoid underestimation of the prevalence, morbidity, mortality and related resource utilisation from this burgeoning chronic disease.
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Affiliation(s)
- Kelly L Hayward
- Centre for Liver Disease Research, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Amy L Johnson
- Centre for Liver Disease Research, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Benjamin J Mckillen
- Centre for Liver Disease Research, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Niall T Burke
- Centre for Liver Disease Research, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Vikas Bansal
- Centre for Liver Disease Research, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Leigh U Horsfall
- Centre for Liver Disease Research, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Gunter Hartel
- Statistics, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Chris Moser
- Statistical Services Branch, Queensland Government Department of Health and Ageing, Brisbane, Queensland, Australia
| | - Elizabeth E Powell
- Centre for Liver Disease Research, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Patricia C Valery
- Centre for Liver Disease Research, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia .,Cancer and Chronic Disease Research Group, QIMR Berghofer Medical Research Institute, Herson, Queensland, Australia
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Chen Z, Babcock A, Sanogo V, Nelson DR, Xiao H, Diaby V. Predictors of 30-day readmission and hospitalization costs of patients with hepatic encephalopathy in the US from 2010 to 2014. Expert Rev Pharmacoecon Outcomes Res 2021; 22:409-415. [PMID: 33985399 DOI: 10.1080/14737167.2021.1927717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Background: Hepatic encephalopathy (HE) is a complex and reversible neuropsychiatric syndrome that is associated with growing, substantial healthcare resource utilization. We aim to examine the predictors of 30-day readmission and hospitalization cost associated with HE.Research design and methods: We conducted a cross-sectional study using the Nationwide Readmissions Database from 2010 to 2014. We assessed the readmission rates using multivariate logistic regression and established temporal trends of readmission rates and hospitalization cost. Weighted hierarchical logistic regression and generalized linear mixed models were used to identify predictors for nationally representative readmissions and hospitalization costs, respectively.Results: The number of index hospitalizations with HE increased with a significant trend from 34,967 in 2010 to 44,791 in 2014. 16.8% of patients were readmitted within 30 days. Predictors increasing readmission risk included female sex, Elixhauser readmission score < 25, elective admission, patient's state residential status, privately insured, number of diagnoses >13, and length of stay >4 days.Conclusions: Our results indicate there is a need to implement better management strategies to improve outcomes in patients hospitalized with HE to curb the increase in the economic burden associated with the disease.
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Affiliation(s)
- Ziyan Chen
- Department of Pharmaceutical Outcomes & Policy (POP), College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Aram Babcock
- Department of Pharmaceutical Outcomes & Policy (POP), College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Vassiki Sanogo
- Department of Pharmaceutical Outcomes & Policy (POP), College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - David R Nelson
- Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Hong Xiao
- Bristol-Myers Squibb, Lawrenceville, NJ, USA
| | - Vakaramoko Diaby
- Department of Pharmaceutical Outcomes & Policy (POP), College of Pharmacy, University of Florida, Gainesville, FL, USA
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Teh KB, Loo JH, Tam YC, Wong YJ. Efficacy and safety of albumin infusion for overt hepatic encephalopathy: A systematic review and meta-analysis. Dig Liver Dis 2021; 53:817-823. [PMID: 34011479 DOI: 10.1016/j.dld.2021.04.030] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS The efficacy and safety of albumin infusion for treatment and prevention of overt hepatic encephalopathy (OHE) among cirrhosis patients remained controversial. We performed a systematic review and meta-analysis to evaluate the benefit of albumin infusion for the treatment and prevention of OHE. METHODS We performed a systematic search of 4 electronic databases up to 31st January 2021. The primary outcome was the resolution of OHE. Secondary outcomes were inpatient mortality and albumin-associated adverse events. We assessed the pooled odds' risk, pooled mean differences, 95% confidence interval and heterogeneity using Review Manager Version 5.3. RESULTS A total of 12 studies (2,087 subjects) were identified. Among cirrhosis patients with OHE, albumin infusion was associated with a lower pooled risk of OHE (OR=0.43, 95%CI: 0.27, 0.68; I2=0%). Among patients without baseline OHE, albumin infusion was associated with a lower pooled risk of developing OHE (OR=0.53, 95%CI: 0.32, 0.86; I2=62%). Albumin infusion was associated with a lower pooled risk of inpatient mortality (OR=0.36, 95%CI: 0.21, 0.60; I2=0%). CONCLUSION Well-powered randomized trials are required to confirm the benefits of albumin infusion for the prevention and treatment of overt hepatic encephalopathy among decompensated cirrhosis patients.
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Affiliation(s)
- Kok Ban Teh
- Department of Gastroenterology & Hepatology, Changi General Hospital, Singapore
| | - Jing Hong Loo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yew Chong Tam
- Department of Medicine, Singapore General Hospital, Singapore
| | - Yu Jun Wong
- Department of Gastroenterology & Hepatology, Changi General Hospital, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Duke-NUS Academic Medicine Programme, Singhealth, Singapore.
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Prevalence of Hepatic Encephalopathy from a Commercial Medical Claims Database in the United States. Int J Hepatol 2021; 2021:8542179. [PMID: 34211786 PMCID: PMC8208864 DOI: 10.1155/2021/8542179] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 02/10/2021] [Accepted: 04/02/2021] [Indexed: 01/01/2023] Open
Abstract
INTRODUCTION Hepatic encephalopathy (HE), a complication of cirrhosis, is associated with increased healthcare resource utilization and mortality, and impaired quality of life. Information on the prevalence of HE in the US general population is limited. METHODS Prevalence of HE was estimated by sequential stepwise data analysis of the Symphony Health anonymized patient-level data (APLD) claims database. First, patients ≥ 18 years with International Classification of Diseases ninth/tenth edition, clinical modification (ICD-9/10-CM), and codes for cirrhosis from 2018 medical and hospital claims were used to estimate prevalence of cirrhosis within the data set and number of patients with cirrhosis in the US general population. Second, patients diagnosed with cirrhosis in the APLD data set from 2015-2016 with an HE ICD-9/10-CM code within 1 year of cirrhosis diagnosis were used to deduce the prevalence of HE within the data set and estimate the number of patients with HE in the US general population. Last, US DiagnosticSource data on serum ammonia level laboratory results measured within ±2 days of a confirmed HE event were merged with the APLD HE data set, then applied to the US general population. RESULTS Medical and hospital claims data were available for 272,256 patients with cirrhosis in 2018. An estimated 536,856 US adults had a diagnosis of cirrhosis (prevalence of 0.21%) in 2018. This proportion applied to the estimated number of patients with cirrhosis in the United States resulted in a prevalence estimate of 201,858 cirrhosis patients with HE in 2018. When factoring in serum ammonia data, prevalence was conservatively estimated as approximately 196,000 cirrhosis patients with HE and serum ammonia levels > 21 μmol/L. CONCLUSIONS In this longitudinal cohort-based study, it was estimated that ≈202,000 patients had HE in the United States in 2018, representing a considerable burden to society and payers.
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Schnelle ANW, Richardson LT, Pettit ME, DeMorrow S, Solouki T. Trihydroxycholanoyl-taurine in brains of rodents with hepatic encephalopathy. JOURNAL OF MASS SPECTROMETRY : JMS 2021; 56:e4729. [PMID: 33942437 DOI: 10.1002/jms.4729] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/22/2021] [Accepted: 04/01/2021] [Indexed: 06/12/2023]
Abstract
Hepatic encephalopathy (HE), a neurological disease resulting from liver failure, is difficult to manage and its causes are unclear. Bile acids have been postulated to be involved in the provenance and progression of various diseases including HE. Hence, the characterization of bile acid profiles in the brains of subjects with and without liver failure can provide important clues for the potential treatment of HE. Nanoflow ultra-performance liquid chromatography electrospray ionization ion mobility mass spectrometry (UPLC-ESI-IM-MS) is a highly sensitive method for detection of specific molecules, such as bile acids in brain samples, at biologically relevant concentrations. We used UPLC-ESI-IM-MS to characterize bile acid profiles in brain samples from seven "healthy" control rodents and 22 "diseased" rodents with liver failure (i.e., induced HE). An isomer of trihydroxycholanoyl-taurine was detected in brain tissue samples from both rats and mice with induced HE; however, this isomer was not detected in the brains of healthy rats and mice. Our findings were confirmed by comparing IM arrival times (AT), exact mass measurements (m/z), and mass spectral fragmentation patterns of the experimentally observed suspected species to standards of trihydroxycholanoyl-taurine isomers. Moreover, In Silico Fractionation was employed to provide an additional analytical dimension to verify bile acid identifications.
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Affiliation(s)
- Amy N W Schnelle
- Department of Chemistry and Biochemistry, Baylor University, Waco, Texas, 76798, USA
| | - Luke T Richardson
- Department of Chemistry and Biochemistry, Baylor University, Waco, Texas, 76798, USA
| | - Michael E Pettit
- Department of Chemistry and Biochemistry, Baylor University, Waco, Texas, 76798, USA
- BioTherapeutics Analytical Development, Janssen Research and Development, LLC, 200 Great Valley Parkway, Malvern, Pennsylvania, 19355, USA
| | - Sharon DeMorrow
- Research Services, Central Texas Veterans Health Care System, Temple, Texas, 76504, USA
- Pharmacology and Toxicology Division, College of Pharmacy, University of Texas at Austin, Austin, Texas, 78712, USA
- Department of Internal Medicine, Dell Medical School, University of Texas at Austin, Austin, Texas, 78712, USA
| | - Touradj Solouki
- Department of Chemistry and Biochemistry, Baylor University, Waco, Texas, 76798, USA
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Chang C, Huang CH, Tseng HJ, Yang FC, Chien RN. Real-World Experience of the One-Year Efficacy of Rifaximin Add-On to Lactulose Is Superior to Lactulose Alone in Patients with Cirrhosis Complicated with Recurrent Hepatic Encephalopathy in Taiwan. J Pers Med 2021; 11:478. [PMID: 34071787 PMCID: PMC8226737 DOI: 10.3390/jpm11060478] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/21/2021] [Accepted: 05/21/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE), a neuropsychiatric complication of decompensated cirrhosis, is associated with high mortality and high risk of recurrence. Rifaximin add-on to lactulose for 3 to 6 months is recommended for the prevention of recurrent episodes of HE after the second episode. However, whether the combination for more than 6 months is superior to lactulose alone in the maintenance of HE remission is less evident. Therefore, the aim of this study is to evaluate the one-year efficacy of rifaximin add-on to lactulose for the maintenance of HE remission in Taiwan. METHODS We conducted a real-world single-center retrospective cohort study to compare the long-term efficacy of rifaximin add-on to lactulose (group R + L) versus lactulose alone (group L, control group). Furthermore, the treatment efficacy before and after rifaximin add-on to lactulose was also analyzed. The primary endpoint of our study was time to first HE recurrence (Conn score ≥ 2). All patients were followed up every three months until death, and censored at one year if still alive. RESULTS AND CONCLUSIONS 12 patients were enrolled in group R + L. Another 31 patients were stratified into group L. Sex, comorbidity, ammonia level, and ascites grade were matched while age, HE grade, and model for end-stage liver disease (MELD) score were adjusted in the multivariable logistic regression model. Compared with group L, significant improvement in the maintenance of HE remission and decreased episodes and days of HE-related hospitalizations were demonstrated in group R + L. The serum ammonia levels were significantly lower at the 3rd and 6th month in group 1. Concerning changes before and after rifaximin add-on in group R + L, mini-mental status examination (MMSE), episodes of hospitalization, and variceal bleeding also improved at 6 and 12 months. Days of hospitalization, serum ammonia levels also improved at 6th month. Except for concern over price, no patients discontinued rifaximin due to adverse events or complications. The above results provide evidence for the one-year use of rifaximin add-on to lactulose in reducing HE recurrence and HE-related hospitalization for patients with decompensated cirrhosis.
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Affiliation(s)
- Ching Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan; (C.C.); (C.-H.H.); (F.-C.Y.)
| | - Chien-Hao Huang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan; (C.C.); (C.-H.H.); (F.-C.Y.)
- College of Medicine, Chang-Gung University, Taoyuan 33305, Taiwan
| | - Hsiao-Jung Tseng
- Biostatistics Unit, Clinical Trial Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan;
| | - Fang-Chen Yang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan; (C.C.); (C.-H.H.); (F.-C.Y.)
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan; (C.C.); (C.-H.H.); (F.-C.Y.)
- College of Medicine, Chang-Gung University, Taoyuan 33305, Taiwan
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Podymova SD. [New approaches to the pathogenesis, clinic, and treatment of hepatic encephalopathy]. TERAPEVT ARKH 2021; 93:236-242. [PMID: 36286643 DOI: 10.26442/00403660.2021.02.200613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 04/06/2021] [Indexed: 11/22/2022]
Abstract
This review article presents new approaches to the assessment of key pathogenesis factors, clinical features, and treatment of hepatic encephalopathy (HE) associated with liver cirrhosis. Various clinical variants of the course of HE in patients with cirrhosis of the liver areconsidered, which are important for the choice of treatment and prevention of repeated relapses of HE. Analyzed the ammonia hypothesis of pathogenesis and associated hyperammonemia, which is the basis of most modern treatment methods. These data on the activation of the adaptive pathway for removing ammonia in the form of glutamine are used in the further study of drugs that enhance the clearance of ammonia. The possibility of reducing GABA-ergic tone due to the effect of the antagonist on the neurosteroid site in the GABA receptor complex is emphasized.
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Affiliation(s)
- S D Podymova
- Loginov Moscow Clinical Research and Practical Center
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40
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Rega D, Aiko M, Peñaranda N, Urios A, Gallego JJ, Giménez-Garzó C, Casanova F, Fiorillo A, Cabrera-Pastor A, San-Miguel T, Ipiens C, Escudero-García D, Tosca J, Montón C, Ballester MP, Ballester J, Aparicio L, Ríos MP, Durbán L, Mir A, Kosenko E, Cases P, Felipo V, Montoliu C. Patients with Minimal Hepatic Encephalopathy Show Altered Thermal Sensitivity and Autonomic Function. J Clin Med 2021; 10:jcm10020239. [PMID: 33440769 PMCID: PMC7826803 DOI: 10.3390/jcm10020239] [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: 10/28/2020] [Revised: 12/30/2020] [Accepted: 01/05/2021] [Indexed: 12/21/2022] Open
Abstract
Cirrhotic patients may experience alterations in the peripheral nervous system and in somatosensory perception. Impairment of the somatosensory system could contribute to cognitive and motor alterations characteristic of minimal hepatic encephalopathy (MHE), which affects up to 40% of cirrhotic patients. We assessed the relationship between MHE and alterations in thermal, vibration, and/or heat pain sensitivity in 58 cirrhotic patients (38 without and 20 with MHE according to Psychometric Hepatic Encephalopathy Score) and 39 controls. All participants underwent attention and coordination tests, a nerve conduction study, autonomic function testing, and evaluation of sensory thresholds (vibration, cooling, and heat pain detection) by electromyography and quantitative sensory testing. The detection thresholds for cold and heat pain on the foot were higher in patients with, than those without MHE. This hyposensitivity was correlated with attention deficits. Reaction times in the foot were longer in patients with, than without MHE. Patients with normal sural nerve amplitude showed altered thermal sensitivity and autonomic function, with stronger alterations in patients with, than in those without MHE. MHE patients show a general decrease in cognitive and sensory abilities. Small fibers of the autonomic nervous system and thermal sensitivity are altered early on in MHE, before large sensory fibers. Quantitative sensory testing could be used as a marker of MHE.
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Affiliation(s)
- Dalia Rega
- INCLIVA, Health Research Institute, 46010 Valencia, Spain (A.U.); (J.-J.G.); (F.C.); (A.F.); (A.C.-P.); (M.-P.B.)
| | - Mika Aiko
- Servicio de Neurofisiología, Hospital Clínico de Valencia, 46010 Valencia, Spain; (M.A.); (N.P.); (C.I.); (P.C.)
| | - Nicolás Peñaranda
- Servicio de Neurofisiología, Hospital Clínico de Valencia, 46010 Valencia, Spain; (M.A.); (N.P.); (C.I.); (P.C.)
| | - Amparo Urios
- INCLIVA, Health Research Institute, 46010 Valencia, Spain (A.U.); (J.-J.G.); (F.C.); (A.F.); (A.C.-P.); (M.-P.B.)
| | - Juan-José Gallego
- INCLIVA, Health Research Institute, 46010 Valencia, Spain (A.U.); (J.-J.G.); (F.C.); (A.F.); (A.C.-P.); (M.-P.B.)
| | - Carla Giménez-Garzó
- Laboratorio de Neurobiología. Centro Investigación Príncipe Felipe, 46012 Valencia, Spain; (C.G.-G.); (V.F.)
| | - Franc Casanova
- INCLIVA, Health Research Institute, 46010 Valencia, Spain (A.U.); (J.-J.G.); (F.C.); (A.F.); (A.C.-P.); (M.-P.B.)
| | - Alessandra Fiorillo
- INCLIVA, Health Research Institute, 46010 Valencia, Spain (A.U.); (J.-J.G.); (F.C.); (A.F.); (A.C.-P.); (M.-P.B.)
| | - Andrea Cabrera-Pastor
- INCLIVA, Health Research Institute, 46010 Valencia, Spain (A.U.); (J.-J.G.); (F.C.); (A.F.); (A.C.-P.); (M.-P.B.)
| | - Teresa San-Miguel
- Departamento de Patología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain;
| | - Cristina Ipiens
- Servicio de Neurofisiología, Hospital Clínico de Valencia, 46010 Valencia, Spain; (M.A.); (N.P.); (C.I.); (P.C.)
| | - Desamparados Escudero-García
- Servicio de Medicina Digestiva, Hospital Clinico de Valencia, 46010 Valencia, Spain; (D.E.-G.); (J.T.); (C.M.); (J.B.)
- Departamento de Medicina, Universidad de Valencia, 46010 Valencia, Spain;
| | - Joan Tosca
- Servicio de Medicina Digestiva, Hospital Clinico de Valencia, 46010 Valencia, Spain; (D.E.-G.); (J.T.); (C.M.); (J.B.)
| | - Cristina Montón
- Servicio de Medicina Digestiva, Hospital Clinico de Valencia, 46010 Valencia, Spain; (D.E.-G.); (J.T.); (C.M.); (J.B.)
| | - María-Pilar Ballester
- INCLIVA, Health Research Institute, 46010 Valencia, Spain (A.U.); (J.-J.G.); (F.C.); (A.F.); (A.C.-P.); (M.-P.B.)
- Servicio de Medicina Digestiva, Hospital Clinico de Valencia, 46010 Valencia, Spain; (D.E.-G.); (J.T.); (C.M.); (J.B.)
| | - José Ballester
- Servicio de Medicina Digestiva, Hospital Clinico de Valencia, 46010 Valencia, Spain; (D.E.-G.); (J.T.); (C.M.); (J.B.)
| | - Luis Aparicio
- Departamento de Anatomía y Embriología, Universidad Valencia, 46010 Valencia, Spain;
| | - María-Pilar Ríos
- Servicio de Digestivo, Hospital Arnau de Vilanova, 46015 Valencia, Spain; (M.-P.R.); (L.D.)
| | - Lucía Durbán
- Servicio de Digestivo, Hospital Arnau de Vilanova, 46015 Valencia, Spain; (M.-P.R.); (L.D.)
| | - Amparo Mir
- Departamento de Medicina, Universidad de Valencia, 46010 Valencia, Spain;
| | - Elena Kosenko
- Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia;
| | - Paula Cases
- Servicio de Neurofisiología, Hospital Clínico de Valencia, 46010 Valencia, Spain; (M.A.); (N.P.); (C.I.); (P.C.)
| | - Vicente Felipo
- Laboratorio de Neurobiología. Centro Investigación Príncipe Felipe, 46012 Valencia, Spain; (C.G.-G.); (V.F.)
| | - Carmina Montoliu
- INCLIVA, Health Research Institute, 46010 Valencia, Spain (A.U.); (J.-J.G.); (F.C.); (A.F.); (A.C.-P.); (M.-P.B.)
- Departamento de Patología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain;
- Correspondence: ; Tel.: +34-963-864-381
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de Jong LA, van Schoonhoven AV, Hofstra HS, Postma MJ, van Hoek B. Budget impact of optimizing rifaximin-α use for the prevention of recurrent hepatic encephalopathy in The Netherlands. J Med Econ 2021; 24:1149-1163. [PMID: 34629016 DOI: 10.1080/13696998.2021.1983291] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
AIMS Rifaximin-α as an adjunct to lactulose is reimbursed in the Netherlands for prevention of the third and subsequent episodes of overt Hepatic Encephalopathy (HE) in cirrhotic patients. However, use of rifaximin-α remains limited. This study evaluates the clinical and economic impact of treating all patients eligible under Dutch reimbursement conditions with rifaximin-α as an adjunct to lactulose for the prevention of overt HE in the Netherlands from a hospital and healthcare payer's perspective. MATERIALS AND METHODS A budget impact analysis was performed following national and international guidelines. Resource use was based on Dutch real-world data. HE-related cost inputs were based on the declaration codes, Dutch cost manual, and actual drug list prices. Several sensitivity and scenario analyses were conducted to assess model robustness. RESULTS Treating eligible HE patients with rifaximin-α in addition to lactulose saves €4,487 and costs €249 per patient over a 5-year period compared with lactulose monotherapy from hospital and healthcare payer's perspectives, respectively. In the Netherlands, an estimated 38% of the 2,567 eligible patients are currently being treated with rifaximin-α. Optimizing rifaximin-α use by treating all eligible patients with the rifaximin-α + lactulose could save more than 3,000 hospital admissions, almost 15,000 hospital bed days, and 300 deaths over a 5-year period. Despite increased drug costs, treatment is estimated to result in potential cost savings over a 5-year period of 7.2 million euros from a Dutch hospital perspective. The budget impact is 397,770 euros from a healthcare payer's perspective. CONCLUSIONS Next to a clinical perspective, also from an economic perspective, wider prescription of rifaximin-α adhering to guidelines could be beneficial to reduce costs from a hospital perspective. From a healthcare payer's perspective, costs increase with addition of rifaximin-α due to relative better survival causing relatively higher drug and liver transplantation-related costs.
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Affiliation(s)
- Lisa Aniek de Jong
- Department of Health Sciences, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands
- Asc Academics, Groningen, The Netherlands
| | - Alexander Victor van Schoonhoven
- Department of Health Sciences, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands
- Asc Academics, Groningen, The Netherlands
| | | | - Maarten Jacobus Postma
- Department of Health Sciences, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands
- Asc Academics, Groningen, The Netherlands
- Department of Economics, Econometrics and Finance, Faculty of Economics and Business, University of Groningen, Groningen, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
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Laguna de la Vera AL, Welsch C, Pfeilschifter W, Trebicka J. Gut–liver–brain axis in chronic liver disease with a focus on hepatic encephalopathy. THE COMPLEX INTERPLAY BETWEEN GUT-BRAIN, GUT-LIVER, AND LIVER-BRAIN AXES 2021:159-185. [DOI: 10.1016/b978-0-12-821927-0.00004-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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de Wit K, Schaapman JJ, Nevens F, Verbeek J, Coenen S, Cuperus FJC, Kramer M, Tjwa ETTL, Mostafavi N, Dijkgraaf MGW, van Delden OM, Beuers UHW, Coenraad MJ, Takkenberg RB. Prevention of hepatic encephalopathy by administration of rifaximin and lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt (TIPS): a multicentre randomised, double blind, placebo controlled trial (PEARL trial). BMJ Open Gastroenterol 2020; 7:e000531. [PMID: 33372103 PMCID: PMC7783616 DOI: 10.1136/bmjgast-2020-000531] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 11/12/2020] [Accepted: 11/26/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Cirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post-TIPS hepatic encephalopathy (HE) is a common (20%-54%) and often severe complication. A prophylactic strategy is lacking. METHODS AND ANALYSIS The Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a TIPS (PEARL) trial, is a multicentre randomised, double blind, placebo controlled trial. Patients undergoing covered TIPS placement are prescribed either rifaximin 550 mg two times per day and lactulose 25 mL two times per day (starting dose) or placebo 550 mg two times per day and lactulose 25 mL two times per day from 72 hours before and until 3 months after TIPS placement. Primary endpoint is the development of overt HE (OHE) within 3 months (according to West Haven criteria). Secondary endpoints include 90-day mortality; development of a second episode of OHE; time to development of episode(s) of OHE; development of minimal HE; molecular changes in peripheral and portal blood samples; quality of life and cost-effectiveness. The total sample size is 238 patients and recruitment period is 3 years in six hospitals in the Netherlands and one in Belgium. ETHICS AND DISSEMINATION This study protocol was approved in the Netherlands by the Medical Research Ethics Committee of the Academic Medical Centre, Amsterdam (2018-332), in Belgium by the Ethics Committee Research UZ/KU Leuven (S62577) and competent authorities. This study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Study results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS ClinicalTrials.gov (NCT04073290) and EudraCT database (2018-004323-37).
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Affiliation(s)
- K de Wit
- Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - J J Schaapman
- Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - F Nevens
- Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
| | - J Verbeek
- Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
| | - S Coenen
- Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - F J C Cuperus
- Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - M Kramer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - E T T L Tjwa
- Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - N Mostafavi
- Biostatistics Unit, Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - M G W Dijkgraaf
- Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - O M van Delden
- Interventional Radiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - U H W Beuers
- Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - M J Coenraad
- Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - R B Takkenberg
- Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
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Semmo N, Müllhaupt B, Ruckstuhl L, Magenta L, Clerc O, Torgler R, Semela D. A prospective, multicenter, post-marketing observational study to measure the quality of life of HCV genotype 1 infected, treatment naïve patients suffering from fatigue and receiving 3D regimen: The HEMATITE study. PLoS One 2020; 15:e0241267. [PMID: 33147283 PMCID: PMC7641439 DOI: 10.1371/journal.pone.0241267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 10/08/2020] [Indexed: 01/27/2023] Open
Abstract
Aim Fatigue is the most commonly reported symptom of Hepatitis C Virus (HCV) infected patients and severely impacts their quality of life. The aim of this study was to measure the impact of 3D regimen treatment on the fatigue, daytime physical activity and sleep efficiency of HCV infected patients with fatigue. Methods HEMATITE was an observational, prospective, open-label, single-arm, Swiss multi-centric study in mono-infected HCV genotype 1 patients. The 28 week observation period comprised of 4 weeks preparation, 12 weeks treatment and 12 weeks follow-up. Fatigue was assessed using the fatigue severity scale (FSS) questionnaire. Patients with FSS ≥ 4 (clinically significant fatigue) were included. The activity tracker, ActiGraph GT9X Link®, was used to measure daytime physical activity and sleep efficiency. Outcome analysis was performed on a scaled down intention to treat (sdITT) population, which excluded patients with insufficient tracker data at all study visits and a modified ITT (mITT) population, which consisted of patients with complete tracker data at all study visits. Results Forty of 41 patients in the ITT population had a sustained virologic response 12 weeks post-treatment (SVR12). Mean baseline FSS score was 6.0 for the sdITT population and 5.9 for the mITT population and decreased from baseline to 12 weeks post-treatment by 2.6 (95% confidence interval [CI]: 2.1, 3.1) for the sdITT (n = 37) population and 2.8 (95% CI: 2.2, 3.4) for the mITT (n = 24) population. Mean daytime physical activity or sleep efficiency did not change considerably over the course of the study. Conclusion Measurement by the activity tracker of mean day time physical activity did not show a considerable change from baseline to SVR12 upon treatment with 3D regimen. Nevertheless, a reduction of fatigue as assessed with the validated fatigue severity scale (FSS) was observed, suggesting a causative role of HCV in this extrahepatic manifestation. Trial registration ClinicalTrials.gov identifier:NCT03002818.
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Affiliation(s)
- Nasser Semmo
- Hepatology, Department of BioMedical Research, University of Bern, Bern, Switzerland
| | - Beat Müllhaupt
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | | | | | - Olivier Clerc
- Infectious Diseases Department, Hospital Pourtalès, Neuchâtel, Switzerland
| | | | - David Semela
- Division of Gastroenterology, Kantonsspital St. Gallen, St. Gallen, Switzerland
- * E-mail:
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Strebel H, Haller B, Sohn M, Schepp W, Gundling F. Role of Brain Biomarkers S-100-Beta and Neuron-Specific Enolase for Detection and Follow-Up of Hepatic Encephalopathy in Cirrhosis before, during and after Treatment with L-Ornithine-L-Aspartate. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2020; 27:391-403. [PMID: 33251288 PMCID: PMC7670347 DOI: 10.1159/000507225] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Accepted: 03/08/2020] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Hepatic encephalopathy (HE), in the context of liver cirrhosis, seems to result from low-grade cerebral edema of the astrocytes. Serum brain biomarkers S-100-beta und neuron-specific enolase (NSE) are often elevated in brain injury. We hypothesized that neuromarkers S-100-beta and NSE can be used in the diagnosis of HE, compared with standardized diagnostic tools. MATERIAL AND METHODS A prospective non-randomized intervention study was performed using L-ornithine-L-aspartate (LOLA) for HE treatment. Primary endpoint was the evaluation of neuromarkers S-100-beta and NSE for detection and diagnosis of follow-up of HE. As secondary endpoints, the efficacy of LOLA on the course of HE and the diagnostic role of Portosystemic-Encephalopathy-Syndrome score (PHES) and critical flicker frequency (CFF) were analyzed. For diagnosis of covert (CHE) and overt (OHE) HE, West-Haven criteria (WHC), PHES and CFF were assessed at study entry. LOLA was applied (20 g i.v.) for 6 days. At the end of the study, HE evaluation was repeated. S-100-beta, NSE and ammonia were assessed in each patient before, during and after therapy with LOLA. RESULTS 30 patients were included. At study entry, CHE was diagnosed in 50% and OHE in 50% of all subjects. A total of 25 participants completed the study. After LOLA therapy, deterioration of HE occurred in <11%, while most patients showed improvement (e.g. improved CFF in 79%). No significant correlation with HE severity (as diagnosed by WHC, PHES and CFF) could be demonstrated for any biochemical parameter. In addition, there were no significant changes in brain biomarkers during the treatment period. DISCUSSION While CFF as well as PHES showed good correlation with treatment response, S-100-beta and NSE did not significantly correlate with HE severity compared to proven diagnostic methods, and do not seem reliable biochemical markers for the follow-up under therapy.
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Affiliation(s)
- Hendrik Strebel
- Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Bogenhausen Academic Teaching Hospital, Technical University of Munich, Munich, Germany
- Department for Internal Medicine I, Elblandklinikum, Meißen, Germany
| | - Bernhard Haller
- Institute of Medical Informatics, Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Maximilian Sohn
- Klinik für Allgemein-, Viszeral-, Endokrine und Minimal-invasive Chirurgie, Klinikum Bogenhausen, Technische Universität München, Munich, Germany
| | - Wolfgang Schepp
- Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Bogenhausen Academic Teaching Hospital, Technical University of Munich, Munich, Germany
| | - Felix Gundling
- Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Bogenhausen Academic Teaching Hospital, Technical University of Munich, Munich, Germany
- Department for Gastroenterology, Diabetics and Endocrinology, Kemperhof Hospital, Gemeinschaftsklinikum Mittelrhein, Koblenz, Germany
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Vidal-González J, Quiroga S, Simón-Talero M, Genescà J. Spontaneous portosystemic shunts in liver cirrhosis: new approaches to an old problem. Therap Adv Gastroenterol 2020; 13:1756284820961287. [PMID: 33062057 PMCID: PMC7533929 DOI: 10.1177/1756284820961287] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/02/2020] [Indexed: 02/04/2023] Open
Abstract
Portal hypertension is the main consequence of liver cirrhosis, leading to severe complications such as variceal hemorrhage, ascites or hepatic encephalopathy. As an attempt to decompress the portal venous system, portal flow is derived into the systemic venous system through spontaneous portosystemic shunts (SPSSs), bypassing the liver. In this review, we aim to provide an overview of the published reports in relation to the prevalence and physiopathology behind the appearance of SPSS in liver cirrhosis, as well as the complications derived from its formation and its management. The role of SPSS embolization is specifically discussed, as SPSSs have been assessed as a therapeutic target, mainly for patients with recurrent/persistent hepatic encephalopathy and preserved liver function. Furthermore, different aspects of the role of SPSS in liver transplantation, as well as in candidates for transjugular intrahepatic portosystemic shunt are reviewed. In these settings, SPSS occlusion has been proposed to minimize possible deleterious effects, but results are so far inconclusive.
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Affiliation(s)
- Judit Vidal-González
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Sergi Quiroga
- Radiology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | | | - Joan Genescà
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
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Pathania A, Rawat A, Dahiya SS, Dhanda S, Barnwal RP, Baishya B, Sandhir R. 1H NMR-Based Metabolic Signatures in the Liver and Brain in a Rat Model of Hepatic Encephalopathy. J Proteome Res 2020; 19:3668-3679. [PMID: 32660248 DOI: 10.1021/acs.jproteome.0c00165] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Hepatic encephalopathy (HE) is a debilitating neuropsychiatric complication associated with acute and chronic liver failure. It is characterized by diverse symptoms with variable severity that includes cognitive and motor deficits. The aim of the study is to assess metabolic alterations in the brain and liver using nuclear magnetic resonance (NMR) spectroscopy and subsequent multivariate analyses to characterize metabolic signatures associated with HE. HE was developed by bile duct ligation (BDL) that resulted in hepatic dysfunctions and cirrhosis as shown by liver function tests. Metabolic profiles from control and BDL rats indicated increased levels of lactate, branched-chain amino acids (BCAAs), glutamate, and choline in the liver, whereas levels of glucose, phenylalanine, and pyridoxine were decreased. In brain, the levels of lactate, acetate, succinate, citrate, and malate were increased, while glucose, creatine, isoleucine, leucine, and proline levels were decreased. Furthermore, neurotransmitters such as glutamate and GABA were increased, whereas choline and myo-inositol were decreased. The alterations in neurotransmitter levels resulted in cognitive and motor defects in BDL rats. A significant correlation was found among alterations in NAA/choline, choline/creatine, and NAA/creatine with behavioral deficits. Thus, the data suggests impairment in metabolic pathways such as the tricarboxylic acid (TCA) cycle, glycolysis, and ketogenesis in the liver and brain of animals with HE. The study highlights that metabolic signatures could be potential markers to monitor HE progression and to assess therapeutic interventions.
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Affiliation(s)
- Anjana Pathania
- Department of Biochemistry, Basic Medical Science Block-II, Panjab University, Sector-25, Chandigarh 160014, India
| | - Atul Rawat
- Department of Surgery, IU Health Comprehensive Wound Centre, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.,Centre for Biomedical Magnetic Resonance (CBMR), SGPGIMS Campus, Lucknow, Uttar Pradesh 226014, India
| | - Sitender Singh Dahiya
- Department of Biochemistry, Basic Medical Science Block-II, Panjab University, Sector-25, Chandigarh 160014, India
| | - Saurabh Dhanda
- Department of Biochemistry, Dr. Rajendra Prasad Government Medical College, Kangra at Tanda, Himachal Pradesh 176001, India
| | | | - Bikash Baishya
- Centre for Biomedical Magnetic Resonance (CBMR), SGPGIMS Campus, Lucknow, Uttar Pradesh 226014, India
| | - Rajat Sandhir
- Department of Biochemistry, Basic Medical Science Block-II, Panjab University, Sector-25, Chandigarh 160014, India
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Rao R, Topiwala A. Alcohol use disorders and the brain. Addiction 2020; 115:1580-1589. [PMID: 32112474 DOI: 10.1111/add.15023] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 02/11/2020] [Accepted: 02/25/2020] [Indexed: 12/15/2022]
Abstract
A diagnosis of alcohol use disorder is associated with a higher risk of dementia, but a dose-response relationship between alcohol intake consumption and cognitive impairment remains unclear. Alcohol is associated with a range of effects on the central nervous system at different doses and acts on a number of receptors. Acute disorders include Wernicke's encephalopathy (WE), traumatic brain injury, blackouts, seizures, stroke and hepatic encephalopathy. The most common manifestations of chronic alcohol consumption are Korsakoff's syndrome (KS) and alcohol-related dementia (ARD). There is limited evidence for benefit from memantine in the treatment of ARD, but stronger evidence for the use of high-dose parenteral thiamine in the progression of neuropsychiatric symptoms for WE. Accumulating evidence exists for pharmacological treatment in the prevention of hepatic encephalopathy. Rehabilitation of people with ARD may take several years, and requires an approach that addresses physical and psychosocial factors.
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Affiliation(s)
- Rahul Rao
- Institute of Psychiatry, Psychology and Neuroscience, Department of Old Age Psychiatry, London, UK.,South London and Maudsley NHS Foundation Trust, Psychological Medicine and Older Adults Directorate, London, UK
| | - Anya Topiwala
- University of Oxford, Big Data Institute, Nuffield Department of Population Health
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San Martín-Valenzuela C, Borras-Barrachina A, Gallego JJ, Urios A, Mestre-Salvador V, Correa-Ghisays P, Ballester MP, Escudero-García D, Tosca J, Montón C, Ríos MP, Kosenko E, Felipo V, Tabares-Seisdedos R, Selva-Vera G, Montoliu C. Motor and Cognitive Performance in Patients with Liver Cirrhosis with Minimal Hepatic Encephalopathy. J Clin Med 2020; 9:E2154. [PMID: 32650464 PMCID: PMC7408738 DOI: 10.3390/jcm9072154] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/01/2020] [Accepted: 07/06/2020] [Indexed: 12/28/2022] Open
Abstract
Minimal hepatic encephalopathy (MHE) is associated with mild cognitive impairment and frailty. This study aims to identify cognitive and motor differences in cirrhotic patients with and without MHE, and the correlations between motor signs and cognitive performance. Gait, balance, hand strength and motor speed performance were evaluated in 66 cirrhotic patients (38 without and 28 with MHE, according to the Psychometric Hepatic Encephalopathy Score (PHES). Cognitive performance was measured with the Mini-Mental State Examination, Verbal Fluency Test, Aprendizaje Verbal España-Complutense Test (TAVEC), Wechsler Adult Intelligence Scale III, Hamilton Depression and Anxiety Rating Scale and Functioning Assessment Short Test (FAST). MHE patients performed worse than patients without MHE in cognitive and autonomous functioning, learning and long-term memory, and verbal fluency. The same pattern was found in gait, center of pressure movement, variability of hand strength performance and hand motor speed. In MHE patients, high correlations were found between balance and FAST test, gait velocity and verbal skills, hand strength variability and anxiety and depression, and motor speed and FAST and TAVEC. MHE patients showed worse motor and cognitive performance than patients without MHE. MHE patients could have impaired movement control expressed as bradykinesia, and this reduced motor performance could correlate with cognitive performance.
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Affiliation(s)
- Constanza San Martín-Valenzuela
- Unit of Personal Autonomy, Dependency and Mental Disorder Assessment, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.S.M.-V.); (A.B.-B.); (V.M.-S.); (R.T.-S.)
- Department of Physiotherapy, Faculty of Physiotherapy, University of Valencia, 46010 Valencia, Spain
- Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM, 28029 Madrid, Spain;
| | - Aroa Borras-Barrachina
- Unit of Personal Autonomy, Dependency and Mental Disorder Assessment, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.S.M.-V.); (A.B.-B.); (V.M.-S.); (R.T.-S.)
| | - Juan-José Gallego
- INCLIVA, Health Research Institute, 46010 Valencia, Spain; (J.-J.G.); (A.U.); (M.-P.B.)
| | - Amparo Urios
- INCLIVA, Health Research Institute, 46010 Valencia, Spain; (J.-J.G.); (A.U.); (M.-P.B.)
| | - Víctor Mestre-Salvador
- Unit of Personal Autonomy, Dependency and Mental Disorder Assessment, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.S.M.-V.); (A.B.-B.); (V.M.-S.); (R.T.-S.)
| | - Patricia Correa-Ghisays
- Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM, 28029 Madrid, Spain;
- Faculty of Psychology, University of Valencia, 46010 Valencia, Spain
| | - María-Pilar Ballester
- INCLIVA, Health Research Institute, 46010 Valencia, Spain; (J.-J.G.); (A.U.); (M.-P.B.)
- Digestive Medicine Unit, Hospital Clinico Universitario de Valencia, 46010 Valencia, Spain; (D.E.-G.); (J.T.); (C.M.)
| | - Desamparados Escudero-García
- Digestive Medicine Unit, Hospital Clinico Universitario de Valencia, 46010 Valencia, Spain; (D.E.-G.); (J.T.); (C.M.)
- Department of Medicine, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Joan Tosca
- Digestive Medicine Unit, Hospital Clinico Universitario de Valencia, 46010 Valencia, Spain; (D.E.-G.); (J.T.); (C.M.)
| | - Cristina Montón
- Digestive Medicine Unit, Hospital Clinico Universitario de Valencia, 46010 Valencia, Spain; (D.E.-G.); (J.T.); (C.M.)
| | - María-Pilar Ríos
- Digestive Service, Arnau de Vilanova Hospital, 46015 Valencia, Spain;
| | - Elena Kosenko
- Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia;
| | - Vicente Felipo
- Laboratory of Neurobiology, Príncipe Felipe Research Center, 46012 Valencia, Spain;
| | - Rafael Tabares-Seisdedos
- Unit of Personal Autonomy, Dependency and Mental Disorder Assessment, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.S.M.-V.); (A.B.-B.); (V.M.-S.); (R.T.-S.)
- Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM, 28029 Madrid, Spain;
- Department of Medicine, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Gabriel Selva-Vera
- Unit of Personal Autonomy, Dependency and Mental Disorder Assessment, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; (C.S.M.-V.); (A.B.-B.); (V.M.-S.); (R.T.-S.)
- Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM, 28029 Madrid, Spain;
- Unit of Psychiatry and Psychological Medicine, Hospital Clinico Universitario de Valencia, 46010 Valencia, Spain
| | - Carmina Montoliu
- INCLIVA, Health Research Institute, 46010 Valencia, Spain; (J.-J.G.); (A.U.); (M.-P.B.)
- Department of Pathology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
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Strictures in Crohn's Disease: From Pathophysiology to Treatment. Dig Dis Sci 2020; 65:1904-1916. [PMID: 32279173 DOI: 10.1007/s10620-020-06227-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 03/19/2020] [Indexed: 12/16/2022]
Abstract
Despite recent advances aimed to treat transmural inflammation in Crohn's disease (CD) patients, the progression to a structuring behavior still represents an issue for clinicians. As inflammation becomes chronic and severe, the attempt to repair damaged tissue can result in an excessive production of extracellular matrix components and deposition of connective tissue, thus favoring the formation of strictures. No specific and accurate clinical predictors or diagnostic tools for intestinal fibrosis exist, and to date, no genetic or serological marker is in routine clinical use. Therefore, intestinal fibrosis is usually diagnosed when it becomes clinically evident and strictures have already occurred. Anti-fibrotic agents such as tranilast, peroxisome proliferator-activated receptor gamma agonists, rho kinase inhibitors, and especially mesenchymal stem cell therapy have provided interesting results, but most of the evidence has been derived from studies performed in vitro. Therefore, current therapy of fibrotic strictures relies mainly on endoscopic and surgical procedures. Although its long-term outcomes may be debated, endoscopic balloon dilation appears to be the safest and most effective approach to treat appropriately selected strictures. The use of endoscopic stricturotomy is currently limited by the expertise needed to perform it and by the few data available in the literature. Some good results have been achieved by the positioning of self-expandable metal stents (SEMS). However, there is no concordance regarding the type of stent to use and for how long it should be left in place. The development of new specific SEMS may lead to better outcomes and to an increased use of this alternative in CD-related strictures.
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