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Anand AC, Acharya SK. The Story of Ammonia in Liver Disease: An Unraveling Continuum. J Clin Exp Hepatol 2024; 14:101361. [PMID: 38444405 PMCID: PMC10910335 DOI: 10.1016/j.jceh.2024.101361] [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: 12/10/2023] [Accepted: 02/03/2024] [Indexed: 03/07/2024] Open
Abstract
Hyperammonemia and liver disease are closely linked. Most of the ammonia in our body is produced by transamination and deamination activities involving amino acid, purine, pyrimidines, and biogenic amines, and from the intestine by bacterial splitting of urea. The only way of excretion from the body is by hepatic conversion of ammonia to urea. Hyperammonemia is associated with widespread toxicities such as cerebral edema, hepatic encephalopathy, immune dysfunction, promoting fibrosis, and carcinogenesis. Over the past two decades, it has been increasingly utilized for prognostication of cirrhosis, acute liver failure as well as acute on chronic liver failure. The laboratory assessment of hyperammonemia has certain limitations, despite which its value in the assessment of various forms of liver disease cannot be negated. It may soon become an important tool to make therapeutic decisions about the use of prophylactic and definitive treatment in various forms of liver disease.
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Giuli L, Maestri M, Santopaolo F, Pompili M, Ponziani FR. Gut Microbiota and Neuroinflammation in Acute Liver Failure and Chronic Liver Disease. Metabolites 2023; 13:772. [PMID: 37367929 DOI: 10.3390/metabo13060772] [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: 04/06/2023] [Revised: 05/25/2023] [Accepted: 06/10/2023] [Indexed: 06/28/2023] Open
Abstract
Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of cerebral dysfunction in patients with acute and/or chronic liver disease. However, recent studies demonstrated a key role of neuroinflammation in the development of neurological complications in this setting. Neuroinflammation is characterized by activation of microglial cells and brain secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which alter neurotransmission, leading to cognitive and motor dysfunction. Changes in the gut microbiota resulting from liver disease play a crucial role in the pathogenesis of neuroinflammation. Dysbiosis and altered intestinal permeability, resulting in bacterial translocation and endotoxemia, are responsible for systemic inflammation, which can spread to brain tissue and trigger neuroinflammation. In addition, metabolites derived from the gut microbiota can act on the central nervous system and facilitate the development of neurological complications, exacerbating clinical manifestations. Thus, strategies aimed at modulating the gut microbiota may be effective therapeutic weapons. In this review, we summarize the current knowledge on the role of the gut-liver-brain axis in the pathogenesis of neurological dysfunction associated with liver disease, with a particular focus on neuroinflammation. In addition, we highlight emerging therapeutic approaches targeting the gut microbiota and inflammation in this clinical setting.
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Affiliation(s)
- Lucia Giuli
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Marta Maestri
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Rashidi-Alavijeh J, Nuruzade N, Frey A, Huessler EM, Hörster A, Zeller AC, Schütte A, Schmidt H, Willuweit K, Lange CM. Implications of anaemia and response to anaemia treatment on outcomes in patients with cirrhosis. JHEP Rep 2023; 5:100688. [PMID: 36926273 PMCID: PMC10011825 DOI: 10.1016/j.jhepr.2023.100688] [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: 08/03/2022] [Revised: 12/29/2022] [Accepted: 01/12/2023] [Indexed: 01/30/2023] Open
Abstract
Background & Aims Anaemia is frequently observed in patients with cirrhosis and was identified as a predictor of adverse outcomes, such as increased mortality and occurrence of acute-on-chronic liver failure. To date, the possible effects of iron supplementation on these adverse outcomes are not well described. We therefore aimed to assess the role of iron supplementation in patients with cirrhosis and its capability to improve prognosis. Methods Laboratory diagnostics were performed in consecutive outpatients with cirrhosis admitted between July 2018 and December 2019 to the University Hospital Essen. Associations with transplant-free survival were assessed in regression models. Results A total of 317 outpatients with cirrhosis were included, of whom 61 received a liver transplant (n = 19) or died (n = 42). In multivariate Cox regression analysis, male sex (hazard ratio [HR] = 3.33, 95% CI [1.59, 6.99], p = 0.001), model for end-stage liver disease score (HR = 1.19, 95% CI [1.11, 1.27], p <0.001) and the increase of haemoglobin levels within 6 months (ΔHb6) (HR = 0.72, 95% CI [0.63, 0.83], p <0.001) were associated with transplant-free survival. Regarding the prediction of haemoglobin increase, intake of rifaximin (beta = 0.50, SD beta = 0.19, p = 0.007) and iron supplementation (beta = 0.79, SD beta = 0.26, p = 0.003) were significant predictors in multivariate analysis. Conclusions An increase of haemoglobin levels is associated with improvement of transplant-free survival in patients with cirrhosis. Because the prediction of haemoglobin increase significantly depends on rifaximin and iron supplementation, application of these two medications can have an important impact on the outcome of these patients. Impact and implications Anaemia is very common in patients with cirrhosis and is known to be a predictor of negative outcomes, but little is known about the effect of iron substitution in these individuals. In our cohort, increase of haemoglobin levels improved transplant-free survival of patients with cirrhosis. The increase of haemoglobin levels was mainly induced by iron supplementation and was even stronger in the case of concomitant use of iron and rifaximin. Clinical trial registration UME-ID-10042.
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Key Words
- ACLF, acute-on-chronic liver failure
- AIH, autoimmune hepatitis
- ALT, alanine aminotransferase
- AP, alkaline phosphatase
- AST, aspartate aminotransferase
- CRP, C-reactive protein
- Haemoglobin
- INR, international normalised ratio
- Iron deficiency
- Iron supplementation
- LT, liver transplantation
- Liver transplantation
- MELD, model for end-stage liver disease
- NASH, non-alcoholic steatohepatitis
- NSBBs, non-selective beta blockers
- PBC, primary biliary cholangitis
- PSC, primary sclerosing cholangitis
- Rifaximin
- SSC, secondary sclerosing cholangitis
- TIPS, transjugular intrahepatic portosystemic shunt
- aPTT, activated partial thromboplastin time
- ΔHb3, difference of haemoglobin levels after 3 months
- ΔHb6, difference of haemoglobin levels after 6 months
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Affiliation(s)
- Jassin Rashidi-Alavijeh
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
| | - Nargiz Nuruzade
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
| | - Alexandra Frey
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
| | - Eva-Maria Huessler
- Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Duisburg, Germany
| | - Anne Hörster
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
| | - Amos Cornelius Zeller
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
| | - Andreas Schütte
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
| | - Hartmut Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
| | - Katharina Willuweit
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
| | - Christian Markus Lange
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
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Caraceni P, Vargas V, Solà E, Alessandria C, de Wit K, Trebicka J, Angeli P, Mookerjee RP, Durand F, Pose E, Krag A, Bajaj JS, Beuers U, Ginès P, Napoleone L, Carol M, Avitabile E, Thu AM, Cervera M, Pérez M, Belén Rubio‐Garcia A, Ardiaca A, Vives A, Pich J, Fabrellas N, Zaccherini G, Chiappa MT, Jiménez C, Palacio E, Campion D, Lanzillotti T, Piano S, Nicolao G, Uschner F, Graf_Dirmeier S, Francoz C, Roux O, Esnault V, Helder J, Aban M, Kazankov K, Korenjak M, Kamath P, Abraldes JG, Watson H. The Use of Rifaximin in Patients With Cirrhosis. Hepatology 2021; 74:1660-1673. [PMID: 33421158 PMCID: PMC8518409 DOI: 10.1002/hep.31708] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/10/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both gram-positive and gram-negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double-blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-on-chronic liver failure, and mortality, are therefore eagerly awaited.
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Affiliation(s)
- Paolo Caraceni
- University of BolognaUniversity Hospital S. Orsola‐Malpighi di BolognaBolognaItaly
| | - Victor Vargas
- Hospital Vall d’HebronUniversitat Autònoma de BarcelonaCIEREHDBarcelonaCataloniaSpain
| | - Elsa Solà
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
| | - Carlo Alessandria
- Division of Gastroenterology and HepatologyCittà della Salute e della Scienza HospitalUniversity of TorinoTurinItaly
| | - Koos de Wit
- Amsterdam University Medical CentersAmsterdamthe Netherlands
| | - Jonel Trebicka
- Goethe‐University ‐ Frankfurt am MainFrankfurt am MainGermany,EF‐CLIFBarcelonaCataloniaSpain
| | | | | | | | - Elisa Pose
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
| | - Aleksander Krag
- Department of Gastroenterology and HepatologyOdense University HospitalOdenseDenmark,Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
| | | | - Ulrich Beuers
- Amsterdam University Medical CentersAmsterdamthe Netherlands
| | - Pere Ginès
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
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Lazebnik LB, Golovanova EV, Alekseenko SA, Bueverov AO, Plotnikova EY, Dolgushina AI, Ilchenko LY, Ermolova TV, Tarasova LV, Lee ED, Tsyganova YV, Akhmedov VA, Ageeva EA, Losev VM, Kupriyanova IN, Serikova SN, Korochanskaya NV, Vologzhanina LG, Zimmerman YS, Sas EI, Zhuravel SV, Okovitiy SV, Osipenko MF, Radchenko VG, Soldatova GS, Sitkin SI, Seliverstov PV, Shavkuta GV, Butova EN, Kozhevnikova SA. Russian Consensus “Hyperammonemia in Adults” (Version 2021). EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:97-118. [DOI: 10.31146/1682-8658-ecg-187-3-97-118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Justification Given the large number of reports on the peculiarities of liver lesions during the Sars-Cov-2 infection [1], a team of experts who participated in the 23rd Congress of the Scientific Society of Gastroenterologists of Russia and 15 National Congress of Therapists of November 19, 2020 decided to make additions to the Russian Consensus of “Hyperammonemia in Adults” published early 2020 [2, 3].
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Affiliation(s)
- L. B. Lazebnik
- “Moscow State University of Medicine and Density n. a. A. I. Evdokimov”
| | - E. V. Golovanova
- “Moscow State University of Medicine and Density n. a. A. I. Evdokimov”
| | | | - A. O. Bueverov
- I. M. Sechenov first Moscow state medical university (Sechenov university); Moscow regional research and clinical Institute of M. F. Vladimirsky
| | - E. Yu. Plotnikova
- Federal State Budgetary Institution of Higher Education Kemerovo state medical University of the Ministry of health of Russia
| | - A. I. Dolgushina
- “South-Ural State Medical University” of the Ministry of Health of Russia
| | - L. Yu. Ilchenko
- Pirogov Russian National Research Medical University (RNRMU)
| | - T. V. Ermolova
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - L. V. Tarasova
- BI of HE “The Surgut State University”; “The Chuvashian State University”
| | - E. D. Lee
- Multifocal Medicine Center of The Central Bank of Russian Federation
| | | | - V. A. Akhmedov
- “Omsk State Medical University” of the Ministry of Health
| | | | | | - I. N. Kupriyanova
- “Ural state medical University” of the Ministry of health of the Russian Federation
| | - S. N. Serikova
- State Budgetary Institution of Health Care “Region Clinic Hospital Nr 2” Health Ministry of Krasnodar Region
| | - N. V. Korochanskaya
- State Budgetary Institution of Health Care “Region Clinic Hospital Nr 2” Health Ministry of Krasnodar Region
| | - L. G. Vologzhanina
- “Perm State Medical University named E. A. Wagner” of the Ministry of Health of Russia
| | - Ya. S. Zimmerman
- “Perm State Medical University named E. A. Wagner” of the Ministry of Health of Russia
| | - E. I. Sas
- Military Medical Academy named after S. M. Kirov
| | - S. V. Zhuravel
- “Moscow State University of Medicine and Density n. a. A. I. Evdokimov”; Scientific Research Institute of Emergency Medicine of N. V. Sklifosovskiy of Healthcare Department of Moscow
| | - S. V. Okovitiy
- Saint Petersburg State Chemical Pharmaceutical University (SPCPA)
| | - M. F. Osipenko
- Public budgetary educational institution of higher education “Novosibirsk State Medical University” of the Ministry of Healthcare of the Russia
| | | | | | - S. I. Sitkin
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation; Federal Medical and Biological Agency “State Research Institute of Highly Pure Biopreparations”
| | - P. V. Seliverstov
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - G. V. Shavkuta
- Rostov State Medical University of the Ministry of Health of Russia
| | - E. N. Butova
- Rostov State Medical University of the Ministry of Health of Russia
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Lazebnik LB, Golovanova EV, Turkina SV, Raikhelson KL, Okovityy SV, Drapkina OM, Maev IV, Martynov AI, Roitberg GE, Khlynova OV, Abdulganieva DI, Alekseenko SA, Ardatskaya MD, Bakulin IG, Bakulina NV, Bueverov AO, Vinitskaya EV, Volynets GV, Eremina EY, Grinevich VB, Dolgushina AI, Kazyulin AN, Kashkina EI, Kozlova IV, Konev YV, Korochanskaya NV, Kravchuk YA, Li ED, Loranskaya ID, Makhov VM, Mekhtiev SN, Novikova VP, Ostroumova OD, Pavlov CS, Radchenko VG, Samsonov AA, Sarsenbaeva AS, Sayfutdinov RG, Seliverstov PV, Sitkin SI, Stefanyuk OV, Tarasova LV, Tkachenko EI, Uspensky YP, Fominykh YA, Khavkin AI, Tsyganova YV, Sharhun OO. Non-alcoholic fatty liver disease in adults: clinic, diagnostics, treatment. Guidelines for therapists, third version. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021; 1:4-52. [DOI: 10.31146/1682-8658-ecg-185-1-4-52] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Affiliation(s)
- L. B. Lazebnik
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - E. V. Golovanova
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - S. V. Turkina
- State-funded Educational Establishment of Higher Professional Education «Volgograd State Medical University of the Ministry of Public Health of the Russian Federation»
| | | | - S. V. Okovityy
- Saint Petersburg State Chemical Pharmaceutical University (SPCPA)
| | - O. M. Drapkina
- National Medical Research Center for Therapy and Preventive Medicine of the Russian Ministry of Health
| | - I. V. Maev
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - A. I. Martynov
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - G. E. Roitberg
- Pirogov Russian National Research Medical University; JSC «Medicine»
| | - O. V. Khlynova
- Perm State Medical University named after academician E. A. Vagner Ministry of Health care of Russia
| | | | | | - M. D. Ardatskaya
- Federal State Budgetary Institution “Central Clinical Hospital”, of the Russian Federation Presidential Administration
| | - I. G. Bakulin
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - N. V. Bakulina
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - A. O. Bueverov
- Moscow regional research and clinical Institute of M. F. Vladimirsky
| | | | | | | | | | | | - A. N. Kazyulin
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | | | - I. V. Kozlova
- Saratov State Medical University n. a. V. I. Razumovsky
| | - Yu. V. Konev
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - N. V. Korochanskaya
- Federal State Budgetary Educational Institution of Higher Education Kuban State Medical University Health Ministry of Russian Federation
| | | | - E. D. Li
- Multifunctional medical center of the Bank of Russia
| | - I. D. Loranskaya
- Federal State Budgetary Educational Institution of Further Professional Education “Russian Medical Academy of Continuous Professional Education” of the Ministry of Healthcare of the Russian Federation
| | - V. M. Makhov
- I. M. Sechenov First Moscow Medical State University
| | - S. N. Mekhtiev
- Institute of Professional Retraining of the International Medical Center “SOGAZ”
| | | | - O. D. Ostroumova
- Federal State Budgetary Educational Institution of Further Professional Education “Russian Medical Academy of Continuous Professional Education” of the Ministry of Healthcare of the Russian Federation
| | - Ch. S. Pavlov
- I. M. Sechenov First Moscow Medical State University
| | | | - A. A. Samsonov
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | | | - R. G. Sayfutdinov
- Kazan State Medical Academy — Branch Campus of the Federal State Budgetary Educational Institution of Further Professional Education “Russian Medical Academy of Continuous Professional Education” of the Ministry of Healthcare of the Russian Federation, central scientifi c research laboratory
| | - P. V. Seliverstov
- North-Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - S. I. Sitkin
- North-Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - O. V. Stefanyuk
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation; National Medical Research Center for Therapy and Preventive Medicine of the Russian Ministry of Health
| | | | | | | | | | - A. I. Khavkin
- Pirogov Russian National Research Medical University
| | | | - O. O. Sharhun
- Pirogov Russian National Research Medical University
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Støy S, Laursen TL, Eriksen LL, Grønbæk H, Vilstrup H, Sandahl TD. No Effect in Alcoholic Hepatitis of Gut-Selective, Broad-Spectrum Antibiotics on Bacterial Translocation or Hepatic and Systemic Inflammation. Clin Transl Gastroenterol 2021; 12:e00306. [PMID: 33566559 PMCID: PMC7846454 DOI: 10.14309/ctg.0000000000000306] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION In alcoholic hepatitis (AH), translocation of gut bacteria may drive hepatic macrophage activation and systemic inflammation. We investigated the effect of oral non-absorbable, broad-spectrum antibiotic treatment on bacterial translocation and liver and systemic inflammation in AH. METHODS We consecutively recruited 31 patients with AH. Fourteen were given vancomycin 500 mg, gentamycin 40 mg, and meropenem 500 mg once daily for 7 days. Seventeen patients were a reference group receiving standard-of-care. Circulating markers of bacterial translocation and inflammation were measured at baseline, by day 7 and 90. Gut bacteriome profiling was performed before the intervention and at day 7. RESULTS At study entry, blood lipopolysaccharide-binding protein was multifold higher than normal, remained unchanged at day 7, but decreased at day 90 (P < 0.001) with no difference between the study groups. The macrophage activation markers sCD163 and sCD206 showed the same pattern (P < 0.001, day 90), still without group differences. The systemic inflammation markers tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, and IL-10 showed similar dynamics without group differences. There was no difference in 90-day mortality (total of 6 deaths) between the groups. The remnant gut bacteriome was markedly diversified by the intervention with growth of bacterial species rare for human flora. DISCUSSION In patients with AH, gut-targeted antibiotic treatment does not change markers of bacterial translocation and liver and systemic inflammation. This suggests that bacterial translocation is less important once the inflammatory process is established or that bacteriome reduction is less important than composition.
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Affiliation(s)
- Sidsel Støy
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Rosenblatt R, Yeh J, Gaglio PJ. Long-Term Management: Modern Measures to Prevent Readmission in Patients with Hepatic Encephalopathy. Clin Liver Dis 2020; 24:277-290. [PMID: 32245533 DOI: 10.1016/j.cld.2020.01.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic encephalopathy (HE) is a frequent indication for hospitalization and represents a common manifestation of portal hypertension and decompensated liver disease that contributes to hospital readmissions. Multiple new techniques are being evaluated to assist in preventing readmissions in these high-risk patients. Techniques to improve medication adherence are paramount. The use of telemedicine and on-demand patient assessment is likely to diminish hospitalizations for HE. Wearable technology has the potential to assist in HE diagnosis and prevent HE progression, with an anticipated diminution in hospital readmissions. This article discusses current and potential future techniques to improve outcomes in these vulnerable patients.
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Affiliation(s)
- Russell Rosenblatt
- Department of Medicine, Center for Liver Disease and Transplantation, NY-Presbyterian Hospital, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, PH-14 622 West 168th Street, New York, NY 10032, USA
| | - Johnathan Yeh
- Department of Medicine, Center for Liver Disease and Transplantation, NY-Presbyterian Hospital, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, PH-14 622 West 168th Street, New York, NY 10032, USA
| | - Paul J Gaglio
- Department of Medicine, Center for Liver Disease and Transplantation, NY-Presbyterian Hospital, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, PH-14 622 West 168th Street, New York, NY 10032, USA.
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Awad MMED, El-Deib AERM, Attia FM, Negm M, Soliman MHM, Omar WH. Role of minimal hepatic encephalopathy in road traffic accidents. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2019. [DOI: 10.1186/s41983-019-0055-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Bajaj JS, O’Leary JG, Tandon P, Wong F, Kamath PS, Biggins SW, Garcia-Tsao G, Lai J, Fallon MB, Thuluvath PJ, Vargas HE, Maliakkal B, Subramanian RM, Thacker LR, Reddy KR. Targets to improve quality of care for patients with hepatic encephalopathy: data from a multi-centre cohort. Aliment Pharmacol Ther 2019; 49:1518-1527. [PMID: 31032966 PMCID: PMC6538445 DOI: 10.1111/apt.15265] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 02/14/2019] [Accepted: 03/24/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatic encephalopathy (HE) can adversely affect outcomes in both in-patients and out-patients with cirrhosis. AIM To define targets for improving quality of care in HE management in the multi-centre North American Consortium for End-Stage Liver Disease (NACSELD) cohort. METHOD NACSELD in-patient cohort was analysed for (a) medication-associated precipitants, (b) aspiration pneumonia development, (c) HE medication changes, and (d) 90-day HE recurrence/readmissions. Comparisons were made between patients on no-therapy, lactulose only, rifaximin only or both. Ninety-day HE-readmission analysis was adjusted for MELD score. RESULTS Two thousand eight hundred and ten patients (1102 no-therapy, 659 lactulose, 154 rifaximin, 859 both) were included. HE on admission, and HE rates during hospitalisation were highest in those on lactulose only or dual therapy compared to no-therapy or rifaximin only (P < 0.001). Medications were the most prevalent precipitants (32%; 21% lactulose over/underuse, 5% benzodiazepines, 4% opioids, 1% rifaximin underuse, 1% hypnotics). Patients with medication-associated precipitants had a better prognosis compared to other precipitants. A total of 23% (n = 217) reached grade 3/4 HE, of which 16% developed HE-related aspiration pneumonia. Two thousand four hundred and twenty patients were discharged alive without liver transplant (790 no-therapy, 639 lactulose, 136 rifaximin, 855 both); 12.5% (n = 99) of no-therapy patients did not receive a discharge HE therapy renewal. Ninety-day HE-related readmissions were seen in 16% of patients (9% no-therapy, 9% rifaximin only, lactulose only 18%, dual 21%, <0.001), which persisted despite MELD adjustment (P = 0.009). CONCLUSION Several targets to improve HE management were identified in a large cohort of hospitalised cirrhotic patients. Interventions to decrease medication-precipitated HE, prevention of aspiration pneumonia, and optimisation of HE medications are warranted.
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Affiliation(s)
- Jasmohan S Bajaj
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | | | | | | | | | - Scott W Biggins
- University of Washington, Seattle, WA, USA and University of Denver, Colorado, CO, USA
| | | | - Jennifer Lai
- University of California, San Francisco, CA, USA
| | - Michael B Fallon
- University of Arizona, Phoenix, AZ, USA and University of Texas, Houston, TX, USA
| | | | | | - Benedict Maliakkal
- University of Tennessee, Memphis, TN and University of Rochester, Rochester, NY, USA
| | | | - Leroy R Thacker
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
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Suk KT, Kim DJ. Gut microbiota: novel therapeutic target for nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2019; 13:193-204. [PMID: 30791767 DOI: 10.1080/17474124.2019.1569513] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 01/10/2019] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common and increasing liver diseases worldwide with a prevalence of 20-33%. NAFLD may progress to fibrosis, compensated cirrhosis, advanced cirrhosis, or hepatocellular carcinoma. Despite the increasing prevalence of NAFLD, definitive medical treatment has not been established, with the exception of lifestyle modification with exercise. Because of the direct connection via portal vein between the intestines and the liver (gut-gut microbiota-liver axis), gut microbiota and associated dysbiosis have been known as regulators in the pathophysiology of NAFLD. Area covered: New therapeutic approaches for modulation of gut microbiota have been proposed and the effectiveness of new therapies including probiotics, prebiotics, synbiotics, bile acid regulation, absorbent, and fecal microbiota transplantation have been demonstrated in recent several studies. This review focuses on the available evidences for new therapies modulating gut microbiota in the management and the prevention of NAFLD. Expert commentary: Gut-gut microbiota-liver axis may play an important role in the etiology of many liver diseases, including NAFLD. It is logical to seek the manipulation of this axis, and further studies are required to understand the underlying precise mechanisms of microbiota-modulation on NAFLD.
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Affiliation(s)
- Ki Tae Suk
- a Division of Gastroenterology and Hepatology , Hallym University College of Medicine , Chuncheon , South Korea
| | - Dong Joon Kim
- a Division of Gastroenterology and Hepatology , Hallym University College of Medicine , Chuncheon , South Korea
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Cho MS, Kim SY, Suk KT, Kim BY. Modulation of gut microbiome in nonalcoholic fatty liver disease: pro-, pre-, syn-, and antibiotics. J Microbiol 2018; 56:855-867. [PMID: 30377993 DOI: 10.1007/s12275-018-8346-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/08/2018] [Accepted: 08/21/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common types of liver diseases worldwide and its incidence continues to increase. NAFLD occurs when the body can no longer effectively store excess energy in the adipose tissue. Despite the increasing prevalence of NAFLD, making lifestyle changes, including increased exercise, is often an elusive goal for patients with NAFLD. The liver directly connects to the gut-gastrointestinal milieu via the portal vein, which are all part of the gut-liver axis. Therefore, the gut-microbiome and microbial products have been actively studied as likely key factors in NAFLD pathophysiology. Hence, dysbiosis of the gut microbiome and therapeutic manipulation of the gut-liver axis are being investigated. Novel therapeutic approaches for modulating gut microbiota through the administration of probiotics, prebiotics, synbiotics, and antibiotics have been proposed with numerous promising initial reports on the effectiveness and clinical applications of these approaches. This review delves into the current evidence on novel therapies that modulate gut microbiota and discusses ongoing clinical trials targeting the gut-liver axis for the management and prevention of NAFLD.
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Affiliation(s)
| | - Sang Yeol Kim
- Division of Gastroenterology and Hepatology, College of Medicine, Hallym University, Chuncheon, 24253, Republic of Korea
| | - Ki Tae Suk
- Division of Gastroenterology and Hepatology, College of Medicine, Hallym University, Chuncheon, 24253, Republic of Korea.
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Neff G, Zachry W. Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic Impact of Rifaximin. PHARMACOECONOMICS 2018; 36:809-822. [PMID: 29651649 PMCID: PMC5999147 DOI: 10.1007/s40273-018-0641-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND Hepatic encephalopathy (HE), a common neurologic complication in cirrhosis, is associated with substantial disease and economic burden. Rifaximin is a non-systemic antibiotic that reduces the risk of overt HE recurrence and overt HE-related hospitalizations. OBJECTIVE Our objective was to provide an overview of the direct HE-related costs and cost benefits of rifaximin, lactulose, and rifaximin plus lactulose. METHODS A systematic review of PubMed and relevant meeting abstracts was conducted to identify publications since 1 January 2007 reporting economic data related to HE and rifaximin and/or lactulose. Further, a public database and published literature were used to estimate current costs of hospitalization for overt HE, and potential cost savings of HE-related hospitalizations with rifaximin. The methodological quality of included studies was evaluated using the Drummond checklist. RESULTS A total of 16 reports were identified for inclusion in the systematic review. Globally, HE-related direct costs ranged from $US5370 to $US50,120 annually per patient. Rifaximin was associated with shorter hospital stays and reduced healthcare costs. Rifaximin also has the potential to reduce overt HE-related hospitalization risk by 50% compared with lactulose. Rifaximin was shown to have a favourable pharmacoeconomic profile compared with lactulose (based on the incremental cost-effectiveness ratio). CONCLUSIONS In addition to its clinical benefits (e.g. reduction in the risk of recurrence of overt HE, overt HE-related hospitalizations, favourable adverse event profile), economic data are favourable for the use of rifaximin in patients with a history of overt HE.
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Affiliation(s)
- Guy Neff
- Florida Research Institute, Florida Digestive Health Specialists, Lakewood Ranch, FL, USA.
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14
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Gómez-Hurtado I, Gimenez P, García I, Zapater P, Francés R, González-Navajas JM, Manichanh C, Ramos JM, Bellot P, Guarner F, Such J. Norfloxacin is more effective than Rifaximin in avoiding bacterial translocation in an animal model of cirrhosis. Liver Int 2018; 38:295-302. [PMID: 28834270 DOI: 10.1111/liv.13551] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 08/09/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Norfloxacin administration is useful in preventing bacterial infections in cirrhosis but associated to the generation of resistant species. Rifaximin is known to reach high concentrations in the intestinal lumen without generating relevant resistance in the intestinal flora. Our aim was to compare the effect of Norfloxacin and Rifaximin on intestinal flora composition, bacterial translocation and survival in cirrhotic rats. METHODS Cirrhosis was induced in rats by oral administration of CCl4 . Animals were divided into three groups: only CCl4 (group I, n = 10); CCl4 + Norfloxacin (group II, n = 17) and CCl4 + Rifaximin (group III, n = 14). Gut bacterial composition, bacterial translocation and cytokine levels were measured. RESULTS Forty-one rats were finally included. The incidence of viable and non-viable bacterial translocation was significantly reduced in animals receiving Norfloxacin; Rifaximin also decreased the incidence of viable and non-viable bacterial translocation, but did not reach statistical significance. Serum TNF-α levels were significantly lower in antibiotic groups. Norfloxacin modified intestinal microbiota, depleting significantly more pathobionts than Rifaximin. CONCLUSION Norfloxacin is more effective than Rifaximin in preventing bacterial translocation in rats with cirrhosis probably because of its capacity to reduce pathobionts from intestinal microbiota.
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Affiliation(s)
- Isabel Gómez-Hurtado
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Paula Gimenez
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Irma García
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
| | - Pedro Zapater
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
- Departamento Farmacología Clínica, UMH, Alicante, Spain
| | - Rubén Francés
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
- Departamento Medicina Clínica, UMH, Alicante, Spain
| | - José M González-Navajas
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Chaysavanh Manichanh
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Departamento Gastroenterología, VHIR, Barcelona, Spain
| | - José M Ramos
- Departamento Medicina Interna, HGUA, Alicante, Spain
| | - Pablo Bellot
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Francisco Guarner
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Departamento Gastroenterología, VHIR, Barcelona, Spain
| | - José Such
- Cleveland Clinic, Digestive Disease institute, Abu Dhabi, UAE
- Lerner School of Medicine, Case Western Reserve University, Cleveland, OH, USA
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15
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The Pharmabiotic Approach to Treat Hyperammonemia. Nutrients 2018; 10:nu10020140. [PMID: 29382084 PMCID: PMC5852716 DOI: 10.3390/nu10020140] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 01/22/2018] [Accepted: 01/26/2018] [Indexed: 12/12/2022] Open
Abstract
Ammonia is constantly produced as a metabolic waste from amino acid catabolism in mammals. Ammonia, the toxic waste metabolite, is resolved in the liver where the urea cycle converts free ammonia to urea. Liver malfunctions cause hyperammonemia that leads to central nervous system (CNS) dysfunctions, such as brain edema, convulsions, and coma. The current treatments for hyperammonemia, such as antibiotics or lactulose, are designed to decrease the intestinal production of ammonia and/or its absorption into the body and are not effective, besides being often accompanied by side effects. In recent years, increasing evidence has shown that modifications of the gut microbiota could be used to treat hyperammonemia. Considering the role of the gut microbiota and the physiological characteristics of the intestine, the removal of ammonia from the intestine by modulating the gut microbiota would be an ideal approach to treat hyperammonemia. In this review, we discuss the significance of hyperammonemia and its related diseases and the efficacy of the current management methods for hyperammonemia to understand the mechanism of ammonia transport in the human body. The possibility to use the gut microbiota as pharmabiotics to treat hyperammonemia and its related diseases is also explored.
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Sidhu GS, Go A, Attar BM, Mutneja HR, Arora S, Patel SA. Rifaximin versus norfloxacin for prevention of spontaneous bacterial peritonitis: a systematic review. BMJ Open Gastroenterol 2017; 4:e000154. [PMID: 28944070 PMCID: PMC5606119 DOI: 10.1136/bmjgast-2017-000154] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 06/26/2017] [Accepted: 06/30/2017] [Indexed: 02/07/2023] Open
Abstract
Aim The aim of this systematic review is to evaluate the efficacy and safety of rifaximin in the prophylaxis of spontaneous bacterial peritonitis (SBP) as compared with norfloxacin. Methods We searched MEDLINE, CINAHL, Google Scholar and Cochrane databases from inception to January 2017. Reference lists of articles as well as conference proceedings were manually screened. We included studies that recruited patients with cirrhosis and ascites who met the criteria for primary or secondary SBP prophylaxis as defined by the European Association for the Study of the Liver and American Association for the Study of Liver Diseases. Two independent investigators reviewed the studies for eligibility, extracted the data and assessed study quality using the Cochrane risk of bias tool. The primary outcome was occurrence of SBP. Secondary outcomes included mortality and adverse events with therapy. Results Of the 435 studies identified, a total of five were included for full-text review. Four studies were eligible for the systematic review, three of which were randomised controlled trials and one was a prospective observational study. The population examined in majority of studies was primarily hepatitis C cirrhosis. The results of individual studies indicated either superior efficacy of rifaximin or no statistical difference between rifaximin and norfloxacin for SBP prophylaxis. Conclusions Moderate-quality evidence shows that long-term use of rifaximin appears to be a reasonable alternative to norfloxacin for SBP prevention in hepatitis C cirrhosis.
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Affiliation(s)
| | - Andrew Go
- University of Illinois at Chicago, Chicago, IL, USA
| | - Bashar M Attar
- Cook County Health and Hospitals System, Chicago, IL, USA
| | | | - Shilpa Arora
- Cook County Health and Hospitals System, Chicago, IL, USA
| | - Sanjay A Patel
- Cook County Health and Hospitals System, Chicago, IL, USA
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17
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Beig A, Fine-Shamir N, Lindley D, Miller JM, Dahan A. Advantageous Solubility-Permeability Interplay When Using Amorphous Solid Dispersion (ASD) Formulation for the BCS Class IV P-gp Substrate Rifaximin: Simultaneous Increase of Both the Solubility and the Permeability. AAPS JOURNAL 2017; 19:806-813. [PMID: 28204967 DOI: 10.1208/s12248-017-0052-1] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 01/31/2017] [Indexed: 02/08/2023]
Abstract
Rifaximin is a BCS class IV (low-solubility, low-permeability) drug and also a P-gp substrate. The aims of this work were to assess the efficiency of different rifaximin amorphous solid dispersion (ASDs) formulations in achieving and maintaining supersaturation and to investigate the consequent solubility-permeability interplay. Spray-dried rifaximin ASDs were prepared with different hydrophilic polymers and their ability to achieve and maintain supersaturation was assessed. Then, rifaximin's apparent intestinal permeability was investigated as a function of increasing supersaturation both in vitro using the parallel artificial membrane permeability assay (PAMPA) and in vivo using the single-pass rat intestinal perfusion (SPIP) model. The efficiency of the different ASDs to achieve and maintain supersaturation of rifaximin was found to be highly polymer dependent, and the copovidone/HPC-SL formulation was found to be superior to the other two, allowing supersaturation of 200× that of the crystalline solubility for 20 h. In vitro, rifaximin flux was increased and the apparent permeability was constant as a function of increasing supersaturation level. In vivo, on the other hand, absorption rate coefficient (k a) was first constant as a function of increasing supersaturation, but at 250×, the crystalline solubility k a was doubled, similar to the k a in the presence of the strong P-gp inhibitor GF120918. In conclusion, a new and favorable nature of solubility-permeability interplay was revealed in this work: delivering high supersaturation level of the BCS class IV drug rifaximin via ASD, thereby saturating the drugs' P-gp-mediated efflux transport, led to the favorable unique win-win situation, where both the solubility and the permeability increased simultaneously.
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Affiliation(s)
- Avital Beig
- Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.Box 653, 84105, Beer-Sheva, Israel
| | - Noa Fine-Shamir
- Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.Box 653, 84105, Beer-Sheva, Israel
| | | | - Jonathan M Miller
- AbbVie Inc., North Chicago, Illinois, 60064, USA.,Vertex Pharmaceuticals Inc., 50 Northern Ave, Boston, Massachusetts, 02210, USA
| | - Arik Dahan
- Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.Box 653, 84105, Beer-Sheva, Israel.
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18
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Kang DJ, Kakiyama G, Betrapally NS, Herzog J, Nittono H, Hylemon PB, Zhou H, Carroll I, Yang J, Gillevet PM, Jiao C, Takei H, Pandak WM, Iida T, Heuman DM, Fan S, Fiehn O, Kurosawa T, Sikaroodi M, Sartor RB, Bajaj JS. Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition. Clin Transl Gastroenterol 2016; 7:e187. [PMID: 27560928 PMCID: PMC5543406 DOI: 10.1038/ctg.2016.44] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 07/15/2016] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Rifaximin has clinical benefits in minimal hepatic encephalopathy (MHE) but the mechanism of action is unclear. The antibiotic-dependent and -independent effects of rifaximin need to be elucidated in the setting of MHE-associated microbiota. To assess the action of rifaximin on intestinal barrier, inflammatory milieu and ammonia generation independent of microbiota using rifaximin. METHODS Four germ-free (GF) mice groups were used (1) GF, (2) GF+rifaximin, (3) Humanized with stools from an MHE patient, and (4) Humanized+rifaximin. Mice were followed for 30 days while rifaximin was administered in chow at 100 mg/kg from days 16-30. We tested for ammonia generation (small-intestinal glutaminase, serum ammonia, and cecal glutamine/amino-acid moieties), systemic inflammation (serum IL-1β, IL-6), intestinal barrier (FITC-dextran, large-/small-intestinal expression of IL-1β, IL-6, MCP-1, e-cadherin and zonulin) along with microbiota composition (colonic and fecal multi-tagged sequencing) and function (endotoxemia, fecal bile acid deconjugation and de-hydroxylation). RESULTS All mice survived until day 30. In the GF setting, rifaximin decreased intestinal ammonia generation (lower serum ammonia, increased small-intestinal glutaminase, and cecal glutamine content) without changing inflammation or intestinal barrier function. Humanized microbiota increased systemic/intestinal inflammation and endotoxemia without hyperammonemia. Rifaximin therapy significantly ameliorated these inflammatory cytokines. Rifaximin also favorably impacted microbiota function (reduced endotoxin and decreased deconjugation and formation of potentially toxic secondary bile acids), but not microbial composition in humanized mice. CONCLUSIONS Rifaximin beneficially alters intestinal ammonia generation by regulating intestinal glutaminase expression independent of gut microbiota. MHE-associated fecal colonization results in intestinal and systemic inflammation in GF mice, which is also ameliorated with rifaximin.
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Affiliation(s)
- Dae J Kang
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Genta Kakiyama
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Naga S Betrapally
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - Jeremy Herzog
- Department of Medicine, University of North Carolina, Division of Gastroenterology and Hepatology, Chapel Hill, North Carolina, USA
| | | | - Phillip B Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Ian Carroll
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - Jing Yang
- Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Patrick M Gillevet
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - Chunhua Jiao
- Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Hajime Takei
- Junshin Clinic Bile Acid Institute, Tokyo, Japan
| | - William M Pandak
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Takashi Iida
- Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan
| | - Douglas M Heuman
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Sili Fan
- West Coast Metabolomics Center, University of California, Davis, California, USA
| | - Oliver Fiehn
- West Coast Metabolomics Center, University of California, Davis, California, USA
| | - Takao Kurosawa
- School of Pharmaceutical Science, Health Sciences University of Hokkaido, Tobetsu, Japan
| | - Masoumeh Sikaroodi
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - R B Sartor
- Department of Medicine, University of North Carolina, Division of Gastroenterology and Hepatology, Chapel Hill, North Carolina, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
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L’encéphalopathie hépatique, du diagnostic au traitement en 2016. MEDECINE INTENSIVE REANIMATION 2016. [DOI: 10.1007/s13546-016-1223-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Ponziani FR, Gerardi V, Pecere S, D’Aversa F, Lopetuso L, Zocco MA, Pompili M, Gasbarrini A. Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications. World J Gastroenterol 2015; 21:12322-12333. [PMID: 26604640 PMCID: PMC4649116 DOI: 10.3748/wjg.v21.i43.12322] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/03/2015] [Accepted: 10/17/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial "fingerprint", characterized by the reduced ratio of "good" to "potentially pathogenic" bacteria has recently been outlined, and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover, in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), and, portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic, immune-modulating and anti-inflammatory activity, a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE, and also to prevent the development of SBP, to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality, triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease.
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Sanchez-Delgado J, Miquel M. [Role of rifaximin in the treatment of hepatic encephalopathy]. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 39:282-92. [PMID: 26545947 DOI: 10.1016/j.gastrohep.2015.08.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 08/08/2015] [Accepted: 08/20/2015] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a frequent and serious complication of liver cirrhosis. In addition to correction of the precipitating factors, the most commonly used treatments are non-absorbable disaccharides and rifaximin. Many of the recommendations are based on current clinical practice and there are few randomized controlled trials. Currently, rifaximin should be initiated during an episode of EH if, after 24-48 hours of non-absorbable disaccharide therapy, there is no clinical improvement. In recurrent EH, it is advisable to add rifaximin in patients under non-absorbable disaccharide therapy who develop a new episode. Currently, standard treatment with rifaximin for minimal EH is not recommended. Rifaximin is effective in the acute treatment of overt encephalopathy and in preventing recurrence.
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Affiliation(s)
- Jordi Sanchez-Delgado
- Unitat d'Hepatologia, Servei de l'Aparell Digestiu, Hopsital de Sabadell. Corporació Sanitària Parc Taulí. Universitat Autònoma de Barcelona, Sabadell, Barcelona, España; CIBERehd, Instituto de Salud Carlos III, Madrid, España
| | - Mireia Miquel
- Unitat d'Hepatologia, Servei de l'Aparell Digestiu, Hopsital de Sabadell. Corporació Sanitària Parc Taulí. Universitat Autònoma de Barcelona, Sabadell, Barcelona, España; CIBERehd, Instituto de Salud Carlos III, Madrid, España.
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Patidar KR, Bajaj JS. Covert and Overt Hepatic Encephalopathy: Diagnosis and Management. Clin Gastroenterol Hepatol 2015; 13:2048-61. [PMID: 26164219 PMCID: PMC4618040 DOI: 10.1016/j.cgh.2015.06.039] [Citation(s) in RCA: 141] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 06/30/2015] [Accepted: 06/30/2015] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) is part of a spectrum of neurocognitive changes in cirrhosis. HE is divided into 2 broad categories based on severity: covert hepatic encephalopathy (CHE) and overt hepatic encephalopathy (OHE). CHE has a significant impact on a patient's quality of life, driving performance, and recently has been associated with increased hospitalizations and death. Likewise, OHE is associated with increased rates of hospitalizations and mortality, and poor quality of life. Given its significant burden on patients, care takers, and the health care system, early diagnosis and management are imperative. In addition, focus also should be directed on patient and family member education on the disease progression and adherence to medications. Treatment strategies include the use of nonabsorbable disaccharides, antibiotics (ie, rifaximin), and, potentially, probiotics. Other therapies currently under further investigation include L-ornithine-L-aspartate, ornithine phenylacetate, glycerol phenylbutyrate, molecular adsorbent recirculating system, and albumin infusion.
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Affiliation(s)
- Kavish R Patidar
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia.
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Matoori S, Leroux JC. Recent advances in the treatment of hyperammonemia. Adv Drug Deliv Rev 2015; 90:55-68. [PMID: 25895618 DOI: 10.1016/j.addr.2015.04.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 03/30/2015] [Accepted: 04/13/2015] [Indexed: 02/07/2023]
Abstract
Ammonia is a neurotoxic agent that is primarily generated in the intestine and detoxified in the liver. Toxic increases in systemic ammonia levels predominantly result from an inherited or acquired impairment in hepatic detoxification and lead to potentially life-threatening neuropsychiatric symptoms. Inborn deficiencies in ammonia detoxification mainly affect the urea cycle, an endogenous metabolic removal system in the liver. Hepatic encephalopathy, on the other hand, is a hyperammonemia-related complication secondary to acquired liver function impairment. A range of therapeutic options is available to target either ammonia generation and absorption or ammonia removal. Therapies for hepatic encephalopathy decrease intestinal ammonia production and uptake. Treatments for urea cycle disorders eliminate ammoniagenic amino acids through metabolic transformation, preventing ammonia generation. Therapeutic approaches removing ammonia activate the urea cycle or the second essential endogenous ammonia detoxification system, glutamine synthesis. Recent advances in treating hyperammonemia include using synergistic combination treatments, broadening the indication of orphan drugs, and developing novel approaches to regenerate functional liver tissue. This manuscript reviews the various pharmacological treatments of hyperammonemia and focuses on biopharmaceutical and drug delivery issues.
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Congly SE, Leise MD. Rifaximin for episodic, overt hepatic encephalopathy: the data are catching up to clinical practice, but questions remain. Am J Gastroenterol 2014; 109:598. [PMID: 24698864 DOI: 10.1038/ajg.2013.480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Stephen E Congly
- Liver Unit, Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Michael D Leise
- Department of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota, USA
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Evaluation of rifaximin in Egyptian patients with hepatic encephalopathy. EGYPTIAN LIVER JOURNAL 2013. [DOI: 10.1097/01.elx.0000433599.23047.b1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Patidar KR, Bajaj JS. Antibiotics for the treatment of hepatic encephalopathy. Metab Brain Dis 2013; 28:307-12. [PMID: 23389621 PMCID: PMC3654040 DOI: 10.1007/s11011-013-9383-5] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 01/25/2013] [Indexed: 02/07/2023]
Abstract
The treatment of hepatic encephalopathy (HE) is complex and therapeutic regimens vary according to the acuity of presentation and the goals of therapy. Most treatments for HE rely on manipulating the intestinal milieu and therefore antibiotics that act on the gut form a key treatment strategy. Prominent antibiotics studied in HE are neomycin, metronidazole, vancomycin and rifaximin. For the management of the acute episode, all antibiotics have been tested. However the limited numbers studied, adverse effects (neomycin oto- and nephrotoxicity, metronidazole neurotoxicity) and potential for resistance emergence (vancomycin-resistant enterococcus) has limited the use of most antibiotics, apart from rifaximin which has the greatest evidence base. Rifaximin has also demonstrated, in conjunction with lactulose, to prevent overt HE recurrence in a multi-center, randomized trial. Despite its cost in the US, rifaximin may prove cost-saving by preventing hospitalizations for overt HE. In minimal/covert HE, rifaximin is the only systematically studied antibiotic. Rifaximin showed improvement in cognition, inflammation, quality-of-life and driving simulator performance but cost-analysis does not favor its use at the current time. Antibiotics, especially rifaximin, have a definite role in the management across the spectrum of HE.
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Affiliation(s)
- Kavish R Patidar
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, VA, USA
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Erythromycin versus neomycin in the treatment of hepatic encephalopathy in cirrhosis: a randomized double-blind study. BMC Gastroenterol 2013; 13:13. [PMID: 23324408 PMCID: PMC3551652 DOI: 10.1186/1471-230x-13-13] [Citation(s) in RCA: 10] [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: 05/02/2012] [Accepted: 01/12/2013] [Indexed: 01/19/2023] Open
Abstract
Background Hepatic encephalopathy (HE) is a severe complication in patients with hepatic cirrhosis, which causes numerous hospital admissions and deaths. Antibiotics are the best options in HE treatment, but head-to-head comparisons between these drugs are scarce. Erythromycin combines the antimicrobial effect and prokinetic properties in the same drug, but it has never been used in HE treatment. Our aim was to evaluate the efficacy of erythromycin as an HE treatment. Methods We achieved a randomized controlled trial of adult patients with HE and hepatic cirrhosis admitted in our hospital. After randomization, the subjects received either erythromycin 250 mg or neomycin 1 g orally QID until hospital discharge or prescription of another antibiotic. All subjects were blindly evaluated every day towards quantifying clinical, neuropsychometric, hepatic and renal exams. Statistical analysis was employed to compare the groups and correlate the variables with hospitalization duration. Results 30 patients were evaluated (15 treated with each drug). At hospital admission, the groups were homogeneous, but the erythromycin group subjects achieved a shorter hospitalization stay (p = 0.032) and a more expressive reduction in alanine aminotranspherase levels (p = 0.026). Hospitalization duration was positively correlated with C reactive protein levels measured previous to (p = 0.015) and after treatment (p = 0.01). Conclusions In the sample evaluated erythromycin was associated with significant reductions in hospital stay and in alanine aminotranspherase values. Hospitalization time was positive correlated with C reactive protein levels measured before and after the treatments.
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Kappus MR, Bajaj JS. Covert hepatic encephalopathy: not as minimal as you might think. Clin Gastroenterol Hepatol 2012; 10:1208-19. [PMID: 22728384 DOI: 10.1016/j.cgh.2012.05.026] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 05/30/2012] [Accepted: 05/31/2012] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a serious neuropsychiatric and neurocognitive complication of acute and chronic liver disease. Symptoms are often overt (confusion, disorientation, ataxia, or coma) but can also be subtle (difficulty with cognitive abilities such as executive decision-making and psychomotor speed). There is consensus that HE is characterized as a spectrum of neuropsychiatric symptoms in the absence of brain disease, ranging from overt HE (OHE) to minimal HE (MHE). The West Haven Criteria are most often used to grade HE, with scores ranging from 0-4 (4 being coma). However, it is a challenge to diagnose patients with MHE or grade 1 HE; it might be practical to combine these entities and name them covert HE for clinical use. The severity of HE is associated with the stage of liver disease. Although the pathologic mechanisms of HE are not well understood, they are believed to involve increased levels of ammonia and inflammation, which lead to low-grade cerebral edema. A diagnosis of MHE requires dedicated psychometric tests and neurophysiological techniques rather than a simple clinical assessment. Although these tests can be difficult to perform in practice, they are cost effective and important; the disorder affects patients' quality of life, socioeconomic status, and driving ability and increases their risk for falls and the development of OHE. Patients with MHE are first managed by excluding other causes of neurocognitive dysfunction. Therapy with gut-specific agents might be effective. We review management strategies and important areas of research for MHE and covert HE.
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Affiliation(s)
- Matthew R Kappus
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia 23249, USA
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Zullo A, Hassan C, Ridola L, Lorenzetti R, Campo SM, Riggio O. Rifaximin therapy and hepatic encephalopathy: Pros and cons. World J Gastrointest Pharmacol Ther 2012; 3:62-7. [PMID: 22966484 PMCID: PMC3437447 DOI: 10.4292/wjgpt.v3.i4.62] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Revised: 06/14/2012] [Accepted: 06/20/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is the second most common major complication in cirrhotics and it significantly impacts quality of life. Therapeutic approaches for HE treatment and prevention mainly continue to rely on ammonia-lowering strategies and non-absorbable disaccharides are currently considered the cornerstone therapy. Non-absorbable antibiotics, such as neomycin and paramomycin, are effective in treatment of acute HE episodes but their prolonged use for recurrence prevention is hampered by possible side-effects. To overcome these limitations, rifaximin use has been proposed. Rifaximin has been shown to be not superior to non-absorbable disaccharides for either HE treatment or prevention, with a similar incidence of side-effects. Cirrhosis significantly increases rifaximin absorption and this could be a cause for concern. Following long-term rifaximin therapy, Clostridium difficile colitis has been observed and Candida albicans has been isolated from 20% of patients. In addition, selection of resistant mutants of both Gram-negative and -positive bacteria in the gastrointestinal tract cannot be definitely ruled out. Electrolyte alterations (sodium and potassium) have been reported during rifaximin therapy, a warning for its long-term use in cirrhotics. Moreover, a potential interference with vitamin K production should be considered which could further impair the already altered clotting status of these patients. The therapeutic cost of rifaximin is markedly higher than non-absorbable disaccharides. While waiting for further safety data, caution should be used to limit the use of rifaximin therapy for a very short-term period in selected HE cirrhotics not responding to non-absorbable disaccharides.
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Affiliation(s)
- Angelo Zullo
- Angelo Zullo, Cesare Hassan, Roberto Lorenzetti, Salvatore MA Campo, Gastroenterology and Digestive Endoscopy, Nuovo Regina Margherita Hospital, 00153 Rome, Italy
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Jia JD. Lactulose in the treatment of hepatic encephalopathy: new evidence for an old modality. J Gastroenterol Hepatol 2012; 27:1262-3. [PMID: 22823914 DOI: 10.1111/j.1440-1746.2012.07177.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Bajaj JS, Pinkerton SD, Sanyal AJ, Heuman DM. Diagnosis and treatment of minimal hepatic encephalopathy to prevent motor vehicle accidents: a cost-effectiveness analysis. Hepatology 2012; 55:1164-71. [PMID: 22135042 PMCID: PMC3319334 DOI: 10.1002/hep.25507] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
UNLABELLED Minimal hepatic encephalopathy (MHE) in cirrhosis is associated with impaired driving skills and increased risk of motor vehicle accidents (MVAs). Detection and treatment of MHE has the potential to reduce costs and morbidity associated with MVAs. We conducted a cost-effectiveness analysis to assess the benefits of different strategies of MHE diagnosis and treatment for reducing MVA-related societal costs. The analyses compared five MHE management strategies: (1) presumptive treatment of all cirrhosis patients; (2) diagnosis by neuropsychological exam (NPE) with treatment; (3) diagnosis by standard psychometric tests (SPTs) with treatment; (4) diagnosis by rapid screening using inhibitory control test (ICT) with treatment; and (5) no MHE diagnosis or treatment (status quo). Treatments considered were lactulose or rifaximin, which were assumed to reduce the MVA rate to the level of similarly aged noncirrhosis patients with benefit adjusted for treatment compliance. A Markov model followed a simulated cohort of 1,000 cirrhosis patients without overt hepatic encephalopathy (OHE), from entry into treatment, through MHE development, and later OHE, when they exited the modeled cohort. Follow-up was for 5 years and included biannual MHE testing. The societal cost of a single MVA was estimated at $42,100. All four strategies with lactulose were cost-saving compared with the status quo. Diagnosis with ICT and lactulose was the most cost-effective approach (cost/MVA prevented: $24,454 ICT; $25,470 SPT; $30,469 presumptive treatment and $33,742 NPE). Net program savings over 5 years ranged from $1.7 to 3.6 million depending on the strategy. Rifaximin therapy was not cost-saving at current prices but would become so at a monthly cost of <$353. CONCLUSION Detection of MHE, especially using the ICT, and subsequent treatment with lactulose could substantially reduce societal costs by preventing MVAs.
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Affiliation(s)
- Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA,Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI
| | - Steven D. Pinkerton
- Center for AIDS Intervention Research, Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, WI
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Douglas M. Heuman
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
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Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol 2012; 56:893-9. [PMID: 22173161 PMCID: PMC3307873 DOI: 10.1016/j.jhep.2011.11.013] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 10/26/2011] [Accepted: 11/03/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Liver fibrosis is associated with angiogenesis and leads to portal hypertension. Certain antibiotics reduce complications of liver failure in humans, however, the effects of antibiotics on the pathologic alterations of the disease are not fully understood. The aim of this study was to test whether the non-absorbable antibiotic rifaximin could attenuate fibrosis progression and portal hypertension in vivo, and explore potential mechanisms in vitro. METHODS The effect of rifaximin on portal pressure, fibrosis, and angiogenesis was examined in wild type and Toll-like receptor 4 (TLR4) mutant mice after bile duct ligation (BDL). In vitro studies were carried out to evaluate the effect of the bacterial product and TLR agonist lipopolysaccharide (LPS) on paracrine interactions between hepatic stellate cells (HSC) and liver endothelial cells (LEC) that lead to fibrosis and portal hypertension. RESULTS Portal pressure, fibrosis, and angiogenesis were significantly lower in BDL mice receiving rifaximin compared to BDL mice receiving vehicle. Studies in TLR4 mutant mice confirmed that the effect of rifaximin was dependent on LPS/TLR4 pathway. Fibronectin (FN) was increased in the BDL liver and was reduced by rifaximin administration and thus, was explored further in vitro as a potential mediator of paracrine interactions of HSC and LEC. In vitro, LPS promoted FN production from HSC. Furthermore, HSC-derived FN promoted LEC migration and angiogenesis. CONCLUSIONS These studies expand our understanding of the relationship of intestinal microbiota with fibrosis development by identifying FN as a TLR4 dependent mediator of the matrix and vascular changes that characterize cirrhosis.
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Iadevaia MD, Prete AD, Cesaro C, Gaeta L, Zulli C, Loguercio C. Rifaximin in the treatment of hepatic encephalopathy. Hepat Med 2011; 3:109-17. [PMID: 24367227 PMCID: PMC3846583 DOI: 10.2147/hmer.s11988] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatic encephalopathy is a challenging complication in patients with advanced liver disease. It can be defined as a neuropsychiatric syndrome caused by portosystemic venous shunting, ranging from minimal to overt hepatic encephalopathy or coma. Its pathophysiology is still unclear, although increased levels of ammonia play a key role. Diagnosis of hepatic encephalopathy is currently based on specific tests evaluating the neuropsychiatric state of patients and their quality of life; the severity of hepatic encephalopathy is measured by the West Haven criteria. Treatment of hepatic encephalopathy consists of pharmacological and corrective measures, as well as nutritional interventions. Rifaximin received approval for the treatment of hepatic encephalopathy in 2010 because of its few side effects and pharmacological benefits. The aim of this work is to review the use and efficacy of rifaximin both in acute and long-term management of hepatic encephalopathy. Treatment of overt hepatic encephalopathy involves management of the acute episode as well as maintenance of remission in those patients who have previously experienced an episode, in order to improve their quality of life. The positive effect of rifaximin in reducing health care costs is also discussed.
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Affiliation(s)
- Maddalena Diana Iadevaia
- Department of Internistica Clinica e Sperimentale, F Magrassi e A Lanzara, Hepatogastroenterology Unit, Second University of Naples, Naples, Italy
| | - Anna Del Prete
- Department of Internistica Clinica e Sperimentale, F Magrassi e A Lanzara, Hepatogastroenterology Unit, Second University of Naples, Naples, Italy
| | - Claudia Cesaro
- Department of Internistica Clinica e Sperimentale, F Magrassi e A Lanzara, Hepatogastroenterology Unit, Second University of Naples, Naples, Italy
| | - Laura Gaeta
- Department of Internistica Clinica e Sperimentale, F Magrassi e A Lanzara, Hepatogastroenterology Unit, Second University of Naples, Naples, Italy
| | - Claudio Zulli
- Department of Internistica Clinica e Sperimentale, F Magrassi e A Lanzara, Hepatogastroenterology Unit, Second University of Naples, Naples, Italy
| | - Carmelina Loguercio
- Department of Internistica Clinica e Sperimentale, F Magrassi e A Lanzara, Hepatogastroenterology Unit, Second University of Naples, Naples, Italy
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