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Bouaziz I, Atheymen R, Sellami K, Sahnoun R, Ksouda K, Bahloul E, Affes H, Hammami S, Turki H, Zghal K. Lactulose induced maculo-papular eruption with positive rechallenge: Unusual reaction to this medication. Therapie 2025; 80:354-356. [PMID: 39710543 DOI: 10.1016/j.therap.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/05/2024] [Indexed: 12/24/2024]
Affiliation(s)
- Imen Bouaziz
- Regional Centre of Pharmacovigilance of Sfax, Faculty of Medicine of Sfax, University of Sfax, 3029 Sfax, Tunisia.
| | - Rim Atheymen
- Regional Centre of Pharmacovigilance of Sfax, Faculty of Medicine of Sfax, University of Sfax, 3029 Sfax, Tunisia
| | - Khadija Sellami
- Department of Dermatology, Hedi Chaker University Hospital, 3029 Sfax, Tunisia
| | - Rym Sahnoun
- Regional Centre of Pharmacovigilance of Sfax, Faculty of Medicine of Sfax, University of Sfax, 3029 Sfax, Tunisia
| | - Kamilia Ksouda
- Regional Centre of Pharmacovigilance of Sfax, Faculty of Medicine of Sfax, University of Sfax, 3029 Sfax, Tunisia
| | - Emna Bahloul
- Department of Dermatology, Hedi Chaker University Hospital, 3029 Sfax, Tunisia
| | - Hanen Affes
- Regional Centre of Pharmacovigilance of Sfax, Faculty of Medicine of Sfax, University of Sfax, 3029 Sfax, Tunisia
| | - Serria Hammami
- Regional Centre of Pharmacovigilance of Sfax, Faculty of Medicine of Sfax, University of Sfax, 3029 Sfax, Tunisia
| | - Hamida Turki
- Department of Dermatology, Hedi Chaker University Hospital, 3029 Sfax, Tunisia
| | - Khaled Zghal
- Regional Centre of Pharmacovigilance of Sfax, Faculty of Medicine of Sfax, University of Sfax, 3029 Sfax, Tunisia
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L'Écuyer S, Charbonney E, Carrier FM, Rose CF. Implication of Hypotension in the Pathogenesis of Cognitive Impairment and Brain Injury in Chronic Liver Disease. Neurochem Res 2024; 49:1437-1449. [PMID: 36635437 DOI: 10.1007/s11064-022-03854-z] [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: 07/25/2022] [Revised: 09/23/2022] [Accepted: 12/26/2022] [Indexed: 01/14/2023]
Abstract
The incidence of chronic liver disease is on the rise. One of the primary causes of hospital admissions for patients with cirrhosis is hepatic encephalopathy (HE), a debilitating neurological complication. HE is defined as a reversible syndrome, yet there is growing evidence stating that, under certain conditions, HE is associated with permanent neuronal injury and irreversibility. The pathophysiology of HE primarily implicates a strong role for hyperammonemia, but it is believed other pathogenic factors are involved. The fibrotic scarring of the liver during the progression of chronic liver disease (cirrhosis) consequently leads to increased hepatic resistance and circulatory anomalies characterized by portal hypertension, hyperdynamic circulatory state and systemic hypotension. The possible repercussions of these circulatory anomalies on brain perfusion, including impaired cerebral blood flow (CBF) autoregulation, could be implicated in the development of HE and/or permanent brain injury. Furthermore, hypotensive insults incurring during gastrointestinal bleed, infection, or liver transplantation may also trigger or exacerbate brain dysfunction and cell damage. This review will focus on the role of hypotension in the onset of HE as well as in the occurrence of neuronal cell loss in cirrhosis.
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Affiliation(s)
- Sydnée L'Écuyer
- Hepato-Neuro Laboratory, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900, rue Saint-Denis - Pavillon R, R08.422 Montréal (Québec), Québec, H2X 0A9, Canada
| | - Emmanuel Charbonney
- Department of Medicine, Critical Care Division, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
| | - François Martin Carrier
- Department of Medicine, Critical Care Division, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
- Department of Anesthesiology, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
- Carrefour de l'innovation et santé des populations , Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Christopher F Rose
- Hepato-Neuro Laboratory, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900, rue Saint-Denis - Pavillon R, R08.422 Montréal (Québec), Québec, H2X 0A9, Canada.
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3
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Jhajharia A, Singh S, Jana S, Ashdhir P, Nijhawan S. Intravenous versus oral 'L-ornithine-L-aspartate' in overt hepatic encephalopathy: a randomized comparative study. Sci Rep 2024; 14:11862. [PMID: 38789596 PMCID: PMC11126676 DOI: 10.1038/s41598-024-62293-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
Hepatic encephalopathy (HE), a morbid ordeal affecting chronic liver disease patients always insists for the search of a rational, superior & infallible agent beyond the time-proven standards i.e., Lactulose & Rifaximin. In this RCT, we compared the efficacy of intravenous (IV) L-ornithine-L-aspartate(LOLA) versus Oral LOLA in patients with chronic liver disease(CLD) enduring overt Hepatic Encephalopathy(OHE). 40 CLD patients with OHE were randomly assigned IV or oral LOLA in a 1:1 ratio. Patients were graded for HE and monitored for serum ammonia levels from day 1 to day 5. The aim was to compare IV versus oral LOLA efficacy in HE grades improvement and its correlation with ammonia levels. The study was registered with clinical trials registry-India, CTRI/2020/12/029943. Baseline characteristics of patients in both groups were similar. The mean difference in ammonia levels from day 1 to day 5 was 55.4 ± 32.58 µmol/L in the IV LOLA group and 60.75 ± 13.82 µmol/L in the oral LOLA group (p = 0.511). Significant reductions in ammonia levels were observed from day 1 to day 5 within each group (p < 0.001). HE grade & ammonia correlated positively in both groups. LOLA, regardless of administration route, has demonstrated efficacy in OHE.
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Affiliation(s)
- Ashok Jhajharia
- Department of Gastroenterology, SMS Medical College & Hospital, Jaipur, Rajasthan, 302004, India.
- , House No. 109, Shiv Vihar, VKI, Infront of road number 5, Sikar Road, Jaipur, 302039, India.
| | - Shashank Singh
- Department of Gastroenterology, SMS Medical College & Hospital, Jaipur, Rajasthan, 302004, India
| | - Sangeeta Jana
- Department of Gastroenterology, SMS Medical College & Hospital, Jaipur, Rajasthan, 302004, India
| | - Prachis Ashdhir
- Department of Gastroenterology, SMS Medical College & Hospital, Jaipur, Rajasthan, 302004, India
| | - Sandeep Nijhawan
- Department of Gastroenterology, SMS Medical College & Hospital, Jaipur, Rajasthan, 302004, India
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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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Hammd M, Elghezewi A, Abdulhadi A, Alabid A, Alabid A, Badi Y, Kamal I, Hesham Gamal M, Mohamed Fisal K, Mujtaba M, Sherif A, Frandah W. Efficacy and Safety of Variable Treatment Options in the Prevention of Hepatic Encephalopathy: A Systematic Review and Network Meta-Analysis. Cureus 2024; 16:e53341. [PMID: 38435950 PMCID: PMC10907550 DOI: 10.7759/cureus.53341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2024] [Indexed: 03/05/2024] Open
Abstract
There are no guidelines for the most effective medication to reduce hepatic encephalopathy (HE) or the associated mortality. The purpose of this study is to determine the most effective possible treatment among the single treatment options or the combined treatment options for decreasing the morbidity and mortality of HE. We evaluated the outcomes by various parameters such as the quality of life, reduction in ammonia, all causes of mortality, adverse events, reversal of minimal HE, and development of overt HE. We systematically searched PubMed, Cochrane, Web of Science, and Scopus till the 19th of January 2023 for studies that assess various treatment options for HE. Data were extracted from eligible studies and pooled in a frequentist network meta-analysis as standardized mean difference (SMD) and their 95% confidence interval (CI) using the MetaInsight web-based tool. The Cochrane Tool was used to assess the randomized controlled trials' quality (RCT), while the NIH tool was used to assess the quality of the included cohort studies. Utilizing the R software, the network meta-analysis was conducted. In addition to a significant variation in cases of (Lactulose and Rifaximin) compared with Rifaximin (RR= 0.39, 95% CI [0.17; 0.89]), the results demonstrated a significantly lower incidence of overt HE in (Lactulose and Rifaximin) compared with placebo (RR=0.19, 95% CI [0.09; 0.40]). Most arms demonstrated a statistically significant reduction in the incidence of overt HE compared to albumin and placebo. The results also demonstrated a significant reduction in ammonia between L-ornithine-L-aspartate (LOLA) and probiotics (MD= -19.17, 95% CI [-38.01; -0.32]), as well as a significant difference in the incidence of LOLA compared to placebo (MD= -22.62, 95% CI [-39.16; -6.07]). This network meta-analysis has significant data for managing subclinical HE in people without a history of overt HE. Our analysis showed that (Lactulose and Rifaximin), followed by (Rifaximin and L-carnitine), followed by (Lactulose and Rifaximin with zinc) were the best combinations regarding overt HE. LOLA reduced ammonia best, followed by Nitazoxanide and finally Lactulose. (Lactulose and Nitazoxanide) have the least adverse effects, followed by (Rifaximin and L-carnitine), then Probiotics. Yet, all mortality outcomes and quality of life changes yielded no useful findings. Future studies like RCTs must be done to compare our therapies directly.
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Affiliation(s)
- Mohamed Hammd
- Internal Medicine/Gastroenterology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Abdelwahap Elghezewi
- Internal Medicine/Gastroenterology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Ahmed Abdulhadi
- Internal Medicine, Faculty of Medicine, Tripoli University, Tripoli, LBY
| | - Abdelwahhab Alabid
- Internal Medicine, Faculty of Medicine, Tripoli University, Tripoli, LBY
| | - Abdulfatah Alabid
- Internal Medicine, Faculty of Medicine, Tripoli University, Tripoli, LBY
| | - Yasra Badi
- Internal Medicine, All Saints University School of Medicine, Dominica, USA
| | - Ibrahem Kamal
- General Medicine, Al-Azhar University, Alexandria, EGY
| | - Mohamed Hesham Gamal
- Pharmacology and Therapeutics, Faculty of Pharmacy, Tanta University, Banha, EGY
| | - Khalid Mohamed Fisal
- Pharmacology and Therapeutics, Faculty of Pharmacy, Deraya University, Minia, EGY
| | - Mohamed Mujtaba
- Internal Medicine/Gastroenterology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Ahmed Sherif
- Internal Medicine/Gastroenterology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Wesam Frandah
- Internal Medicine/Gastroenterology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
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Sharma BC, Maharshi S, Sachdeva S, Mahajan B, Sharma A, Bara S, Srivastava S, Kumar A, Dalal A, Sonika U. Nutritional therapy for persistent cognitive impairment after resolution of overt hepatic encephalopathy in patients with cirrhosis: A double-blind randomized controlled trial. J Gastroenterol Hepatol 2023; 38:1917-1925. [PMID: 37354045 DOI: 10.1111/jgh.16266] [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: 02/19/2023] [Revised: 05/27/2023] [Accepted: 06/06/2023] [Indexed: 06/26/2023]
Abstract
BACKGROUND AND AIM Minimal hepatic encephalopathy (MHE) reflects cognitive impairment in patients with liver cirrhosis and is associated with poor prognosis. We assessed the effects of nutritional therapy on cognitive functions, health-related quality of life (HRQOL), anthropometry, endotoxins, and inflammatory markers in cirrhotic patients with MHE. METHODS In a double-blind randomized controlled trial, cirrhotic patients with MHE were randomized to nutritional therapy (group I: 30-35 kcal/kg/day and 1.0-1.5 g of protein/kg/day) and no nutritional therapy (group II: diet as patients were taking before) for 6 months. MHE was diagnosed based on psychometric hepatic encephalopathy score (PHES). Anthropometry, ammonia, endotoxins, inflammatory markers, myostatin, and HRQOL were assessed at baseline and after 6 months. Primary endpoints were improvement or worsening in MHE and HRQOL. RESULTS A total of 150 patients were randomized to group I (n = 75, age 46.3 ± 12.5 years, 58 men) and group II (n = 75, age 45.2 ± 9.3 years, 56 men). Baseline PHES (-8.16 ± 1.42 vs -8.24 ± 1.43; P = 0.54) was comparable in both groups. Reversal of MHE was higher in group I (73.2% vs 21.4%; P = 0.001) than group II. Improvement in PHES (Δ PHES 4.0 ± 0.60 vs -4.18 ± 0.40; P = 0.001), HRQOL (Δ Sickness Impact Profile 3.24 ± 3.63 vs 0.54 ± 3.58; P = 0.001), anthropometry, ammonia, endotoxins, cytokines, and myostatin levels was also significantly higher in group I than group II. Overt hepatic encephalopathy developed in 6 patients in group I and 13 in group II (P = 0.04). CONCLUSIONS Nutritional therapy is effective in treatment of MHE and associated with improvement in nutritional status, HRQOL, ammonia, endotoxins, inflammatory markers, and myostatin levels.
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Affiliation(s)
| | | | - Sanjeev Sachdeva
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | - Bhawna Mahajan
- Department of Biochemistry, G.B. Pant Hospital, New Delhi, India
| | - Ashok Sharma
- Department of Radiology, G.B. Pant Hospital, New Delhi, India
| | - Sushma Bara
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | | | - Ajay Kumar
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | - Ashok Dalal
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | - Ujjwal Sonika
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
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Higuera-de-la-Tijera F, Velarde-Ruiz Velasco J, Raña-Garibay R, Castro-Narro G, Abdo-Francis J, Moreno-Alcántar R, Pérez-Hernández J, Torre A, Contreras-Omaña R, Cano-Contreras A, Castillo-Barradas M, Pérez-Escobar J, Aldana-Ledesma J, Cerda-Reyes E, Fernández-Pérez N, Meza-Cardona J, Flores-García N, Reyes-Bastidas M, Lira-Vera J, García-Jiménez E, Santana-Vargas D, Páez-Zayas V, Chávez-Tapia N, Márquez-Guillén E. Visión actual sobre el diagnóstico y los cuidados integrales en la encefalopatía hepática. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2023; 88:155-174. [DOI: 10.1016/j.rgmx.2023.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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8
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Higuera-de-la-Tijera F, Velarde-Ruiz Velasco JA, Raña-Garibay RH, Castro-Narro GE, Abdo-Francis JM, Moreno-Alcántar R, Pérez-Hernández JL, Torre A, Contreras-Omaña R, Cano-Contreras A, Castillo-Barradas M, Pérez-Escobar J, Aldana-Ledesma JM, Cerda-Reyes E, Fernández-Pérez NJ, Meza-Cardona J, Flores-García NC, Reyes-Bastidas M, Lira-Vera JE, García-Jiménez ES, Santana-Vargas D, Páez-Zayas VM, Chávez-Tapia NC, Márquez-Guillén E. Current vision on diagnosis and comprehensive care in hepatic encephalopathy. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2023; 88:155-174. [PMID: 37127462 DOI: 10.1016/j.rgmxen.2023.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 03/08/2023] [Indexed: 05/03/2023]
Abstract
The first clinical guidelines on hepatic encephalopathy were published in 2009. Almost 14 years since that first publication, numerous advances in the field of diagnosis, treatment, and special condition care have been made. Therefore, as an initiative of the Asociación Mexicana de Gastroenterología A.C., we present a current view of those aspects. The manuscript described herein was formulated by 24 experts that participated in six working groups, analyzing, discussing, and summarizing the following topics: Definition of hepatic encephalopathy; recommended classifications; epidemiologic panorama, worldwide and in Mexico; diagnostic tools; conditions that merit a differential diagnosis; treatment; and primary and secondary prophylaxis. Likewise, these guidelines emphasize the management of certain special conditions, such as hepatic encephalopathy in acute liver failure and acute-on-chronic liver failure, as well as specific care in patients with hepatic encephalopathy, such as the use of medications and types of sedation, describing those that are permitted or recommended, and those that are not.
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Affiliation(s)
- F Higuera-de-la-Tijera
- Departamento de Gastroenterología y Hepatología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico.
| | - J A Velarde-Ruiz Velasco
- Departamento de Gastroenterología, Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
| | | | - G E Castro-Narro
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - R Moreno-Alcántar
- Departamento de Gastroenterología, Hospital de Especialidades Bernardo Sepúlveda del Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - J L Pérez-Hernández
- Departamento de Gastroenterología y Hepatología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - A Torre
- Centro Médico ABC, Mexico City, Mexico
| | - R Contreras-Omaña
- Centro de Educación e Investigación en Enfermedades Hepáticas y Toxicológicas (CEIHET), Pachuca, Hidalgo, Mexico
| | - A Cano-Contreras
- Centro de Investigaciones Médico Biológicas, Universidad Veracruzana, Veracruz, Veracruz, Mexico
| | - M Castillo-Barradas
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional "La Raza", IMSS, Mexico City, Mexico
| | - J Pérez-Escobar
- Instituto Nacional de Enfermedades Respiratorias (INER) "Ismael Cosío Villegas", Mexico City, Mexico
| | - J M Aldana-Ledesma
- Departamento de Gastroenterología, Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
| | - E Cerda-Reyes
- Departamento de Gastroenterología, Hospital Central Militar, Mexico City, Mexico
| | | | | | - N C Flores-García
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - J E Lira-Vera
- Hospital Central "Dr. Ignacio Morones Prieto", San Luis Potosí, Mexico
| | - E S García-Jiménez
- Departamento de Gastroenterología, Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
| | - D Santana-Vargas
- Clínica de Trastornos del Sueño, Departamento de Medicina Experimental, Facultad de Medicina, UNAM, Mexico City, Mexico
| | - V M Páez-Zayas
- Departamento de Gastroenterología y Hepatología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | | | - E Márquez-Guillén
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Killer J, Bunešová VN, Modráčková N, Vlková E, Pechar R, Šplíchal I. Lactulose in combination with soybean lecithin has a cryoprotective effect on probiotic taxa of bifidobacteria and Lactobacillaceae. Lett Appl Microbiol 2023; 76:6993074. [PMID: 36657381 DOI: 10.1093/lambio/ovad008] [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: 08/26/2022] [Revised: 01/05/2023] [Accepted: 01/18/2023] [Indexed: 01/20/2023]
Abstract
Lactulose is commonly used in pharmacy for constipation and hepatic encephalopathy treatment. The prebiotic effect of lactulose is also often mentioned. However, its cryoprotective effect in combination with lecithin on the main representatives of probiotics has not been tested yet. The 12 taxa of bifidobacteria and Lactobacillaceae members were used for the purpose. These were mixed in a ratio of 1:1 with lactulose + lecithin (finally 5.0% and 1.25%, respectively; LL). The 25% glycerol (G+) solution and cultures themselves were applied as positive and negative controls, respectively. Bacterial suspensions were stored at a mild freezing temperature (-20°C) until the end of the experiment (210th day). The LL solution had a comparable (insignificant difference at the P-value = 0.05) cryoprotective effect as the positive control in five of six bifidobacteria and in three of six representatives of Lactobacillaceae. The better cryoprotective effect was revealed in other Lactobacillaceae. At the end of the experiment, the generally accepted therapeutic minimum (>107 Colony Forming Units/mL) was determined in LL solution in five bifidobacteria and four Lactobacillaceae strains. The presented results improve knowledge about long-term mild cryopreservation of the most commonly used probiotics and could contribute to developing new forms of (nutri)synbiotics.
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Affiliation(s)
- Jiří Killer
- Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, v. v. i.; Vídeňská 1083, 142 20 Prague 4-Krč, Czech Republic.,Department of Microbiology, Nutrition and Dietetics, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences, Kamýcká 129, 165 00 Prague 6-Suchdol, Czech Republic
| | - Věra Neužil Bunešová
- Department of Microbiology, Nutrition and Dietetics, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences, Kamýcká 129, 165 00 Prague 6-Suchdol, Czech Republic
| | - Nikol Modráčková
- Department of Microbiology, Nutrition and Dietetics, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences, Kamýcká 129, 165 00 Prague 6-Suchdol, Czech Republic
| | - Eva Vlková
- Department of Microbiology, Nutrition and Dietetics, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences, Kamýcká 129, 165 00 Prague 6-Suchdol, Czech Republic
| | - Radko Pechar
- Department of Microbiology, Nutrition and Dietetics, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences, Kamýcká 129, 165 00 Prague 6-Suchdol, Czech Republic.,Food Research Institute Prague, Radiová 1285/7, 102 00 Prague 10-Hostivař, Czech Republic
| | - Igor Šplíchal
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 549 22 Nový Hrádek, Czech Republic
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Minimal Hepatic Encephalopathy Affects Daily Life of Cirrhotic Patients: A Viewpoint on Clinical Consequences and Therapeutic Opportunities. J Clin Med 2022; 11:jcm11237246. [PMID: 36498820 PMCID: PMC9736966 DOI: 10.3390/jcm11237246] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/27/2022] [Indexed: 12/12/2022] Open
Abstract
Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological testing focused on attention, working memory, psychomotor speed and visuospatial ability. Ideally, each patient should be tested for this condition because, despite the absence of symptoms, it has severe repercussions on daily life activities. It may be responsible for an inability to drive, sleep disturbances, risk of falls and inability to work. Some studies have highlighted its prognostically unfavorable role on mortality and risk of "overt" HE (OHE). Finally, MHE severely affects the lives of patients and caregivers, altering their quality of life and their socioeconomic status. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics, such as rifaximin, probiotics and branched-chain amino acids, with promising results. For this reason, early diagnosis and intervention with appropriate measures is essential, with the aim of improving both performance on psychometric tests, as well as clinical aspects related to this condition.
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11
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Gut Microbiome and Organ Fibrosis. Nutrients 2022; 14:nu14020352. [PMID: 35057530 PMCID: PMC8781069 DOI: 10.3390/nu14020352] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/07/2022] [Accepted: 01/08/2022] [Indexed: 02/07/2023] Open
Abstract
Fibrosis is a pathological process associated with most chronic inflammatory diseases. It is defined by an excessive deposition of extracellular matrix proteins and can affect nearly every tissue and organ system in the body. Fibroproliferative diseases, such as intestinal fibrosis, liver cirrhosis, progressive kidney disease and cardiovascular disease, often lead to severe organ damage and are a leading cause of morbidity and mortality worldwide, for which there are currently no effective therapies available. In the past decade, a growing body of evidence has highlighted the gut microbiome as a major player in the regulation of the innate and adaptive immune system, with severe implications in the pathogenesis of multiple immune-mediated disorders. Gut microbiota dysbiosis has been associated with the development and progression of fibrotic processes in various organs and is predicted to be a potential therapeutic target for fibrosis management. In this review we summarize the state of the art concerning the crosstalk between intestinal microbiota and organ fibrosis, address the relevance of diet in different fibrotic diseases and discuss gut microbiome-targeted therapeutic approaches that are current being explored.
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Faccioli J, Gioia S, Nardelli S, Riggio O, Ridola L. Lactulose in Liver Cirrhosis. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:223-240. [DOI: 10.1007/978-981-19-2615-0_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Moran S, López-Sánchez M, Milke-García MDP, Rodríguez-Leal G. Current approach to treatment of minimal hepatic encephalopathy in patients with liver cirrhosis. World J Gastroenterol 2021; 27:3050-3063. [PMID: 34168407 PMCID: PMC8192295 DOI: 10.3748/wjg.v27.i22.3050] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/01/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Minimal hepatic encephalopathy (MHE) corresponds to the earliest stage of hepatic encephalopathy (HE). MHE does not present clinically detectable neurological-psychiatric abnormalities but is characterized by imperceptible neurocognitive alterations detected during routine clinical examination via neuropsychological or psychometrical tests. MHE may affect daily activities and reduce job performance and quality of life. MHE can increase the risk of accidents and may develop into overt encephalopathy, worsening the prognosis of patients with liver cirrhosis. Despite a lack of consensus on the therapeutic indication, interest in finding novel strategies for prevention or reversion has led to numerous clinical trials; their results are the main objective of this review. Many studies address the treatment of MHE, which is mainly based on the strategies and previous management of overt HE. Current alternatives for the management of MHE include measures to maintain nutritional status while avoiding sarcopenia, and manipulation of intestinal microbiota with non-absorbable disaccharides such as lactulose, antibiotics such as rifaximin, and administration of different probiotics. This review analyzes the results of clinical studies that evaluated the effects of different treatments for MHE.
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Affiliation(s)
- Segundo Moran
- Laboratory of Hepatology Research, Centro Médico Nacional, Siglo XXI, Mexican Institute of Social Security, Mexico City 06720, Mexico
| | - Marlene López-Sánchez
- Laboratory of Hepatology Research, Centro Médico Nacional, Siglo XXI, Mexican Institute of Social Security, Mexico City 06720, Mexico
| | | | - Gustavo Rodríguez-Leal
- Laboratory of Hepatology Research, Centro Médico Nacional, Siglo XXI, Mexican Institute of Social Security, Mexico City 06720, Mexico
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Abstract
Type C hepatic encephalopathy (HE) is a brain dysfunction caused by severe hepatocellular failure or presence of portal-systemic shunts in patients with liver cirrhosis. In its subclinical form, called “minimal hepatic encephalopathy (MHE), only psychometric tests or electrophysiological evaluation can reveal alterations in attention, working memory, psychomotor speed and visuospatial ability, while clinical neurological signs are lacking. The term “covert” (CHE) has been recently used to unify MHE and Grade I HE in order to refer to a condition that is not unapparent but also non overt. “Overt” HE (OHE) is characterized by personality changes, progressive disorientation in time and space, acute confusional state, stupor and coma. Based on its time course, OHE can be divided in Episodic, Recurrent or Persistent. Episodic HE is generally triggered by one or more precipitant factors that should be found and treated. Unlike MHE, clinical examination and clinical decision are crucial for OHE diagnosis and West Haven criteria are widely used to assess the severity of neurological dysfunction. Primary prophylaxis of OHE is indicated only in the patient with gastrointestinal bleeding using non-absorbable antibiotics (Rifaximin) or non-absorbable disaccharides (Lactulose). Treatment of OHE is based on the identification and correction of precipitating factors and starting empirical ammonia-lowering treatment with Rifaximin and Lactulose (per os and enemas). The latter should be used for secondary prophylaxis, adding Rifaximin if HE becomes recurrent. In recurrent/persistent HE, the treatment options include fecal transplantation, TIPS revision and closure of eventual splenorenal shunts. Treatment of MHE should be individualized on a case-by-case basis.
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Beraza N. Fibrosis and the intestinal microbiome; a focus on chronic liver disease. Curr Opin Pharmacol 2020; 49:76-81. [PMID: 31670055 DOI: 10.1016/j.coph.2019.09.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 09/24/2019] [Indexed: 02/07/2023]
Abstract
The role of the microbiome in progression of liver disease is an exciting area of research that is advancing rapidly supported by the development of next-generation sequencing and bioinformatics tools that simultaneously identify the composition and function of the microbiome. Changes in the microbiome are associated with pathogenesis of chronic liver disease; specifically, changes in microbiome composition predict disease severity and specific microbial signatures can be used to distinguish between mild disease, advanced fibrosis and cirrhosis. Future work combining functional metagenomic analysis with preclinical mechanistic studies will be key to advancing our understanding of how the microbiome affects the pathogenesis of different chronic liver disease aetiologies and to identify personalised therapeutics based on modulation of the microbiome and its function.
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Affiliation(s)
- Naiara Beraza
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich, Norfolk, NR4 7UQ, UK.
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Mahpour NY, Pioppo-Phelan L, Reja M, Tawadros A, Rustgi VK. Pharmacologic Management of Hepatic Encephalopathy. Clin Liver Dis 2020; 24:231-242. [PMID: 32245530 DOI: 10.1016/j.cld.2020.01.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Pharmacologic management of hepatic encephalopathy includes a broad range of therapies. This article covers the specific mainstays of therapies, such as antimicrobials and laxatives, with an established evidence base. This article also covers newer modalities of therapies, such as fecal microbiota transplant, probiotics, bioartificial support systems, small molecular therapies such as l-ornithine l-aspartate, branched chain amino acids, l-carnitine, zinc, and other forms of therapy currently under review.
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Affiliation(s)
- Noah Y Mahpour
- Department of Internal Medicine, Robert Wood Johnson School of Medicine, 1 Robert Wood Johnson Place, New Brunswick, NJ 08901, USA
| | - Lauren Pioppo-Phelan
- Department of Internal Medicine, Robert Wood Johnson School of Medicine, 1 Robert Wood Johnson Place, New Brunswick, NJ 08901, USA
| | - Mishal Reja
- Department of Internal Medicine, Robert Wood Johnson School of Medicine, 1 Robert Wood Johnson Place, New Brunswick, NJ 08901, USA
| | - Augustine Tawadros
- Department of Internal Medicine, Robert Wood Johnson School of Medicine, 1 Robert Wood Johnson Place, New Brunswick, NJ 08901, USA
| | - Vinod K Rustgi
- Center for Liver Diseases and Liver Masses, Robert Wood Johnson School of Medicine, MedEd Building, Room 466, 1 Robert Wood Johnson Place, New Brunswick, NJ 08901, USA.
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17
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Dhiman RK, Thumburu KK, Verma N, Chopra M, Rathi S, Dutta U, Singal AK, Taneja S, Duseja A, Singh M. Comparative Efficacy of Treatment Options for Minimal Hepatic Encephalopathy: A Systematic Review and Network Meta-Analysis. Clin Gastroenterol Hepatol 2020; 18:800-812.e25. [PMID: 31476436 DOI: 10.1016/j.cgh.2019.08.047] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/07/2019] [Accepted: 08/09/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We aimed to synthesize evidence for most effective treatments for minimal hepatic encephalopathy (HE) and prevention of overt HE in patients with cirrhosis. METHODS We performed a systematic search of the PubMed, EMBASE, OvidSP, and Cochrane Central Register of Controlled Trials databases through July 26, 2018, for randomized controlled trials evaluating treatments for minimal HE in patients with cirrhosis, with primary outcomes of reversal of minimal HE or prevention of overt HE. We conducted a meta-analysis and then used network meta-analysis and surface under cumulated ranking (SUCRA) to pool the direct and indirect estimates and rank the different treatments. We appraised study quality using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS Our meta-analysis and network meta-analysis included 25 trials, comprising 1563 participants. Agents found to be effective in reversing minimal HE compared with placebo or no treatment included rifaximin (odds ratio [OR], 7.53; 95% predictive interval [PrI], 4.45-12.73; SUCRA, 89.2%; moderate quality), lactulose (OR, 5.39; 95% PrI, 3.60-8.0; SUCRA, 67.2%; moderate quality), the combination of probiotics and lactulose (OR, 4.66; 95% PrI, 1.90-11.39; SUCRA, 52.4%; low quality), L-ornithine L-aspartate (OR, 4.45; 95% PrI, 2.67-7.42; SUCRA, 47.2%; low moderate quality), and probiotics (OR, 3.89; 95% PrI, 2.52-6.02; SUCRA, 34.1%; low quality). Agents found to be effective in preventing episodes of overt HE compared with placebo or no treatment included L-ornithine L-aspartate (OR, 0.19; 95% PrI, 0.04-0.91; SUCRA, 75.1%; high moderate quality), lactulose (OR, 0.22; 95% PrI, 0.09-0.52; SUCRA, 73.9%; moderate quality), and probiotics (OR, 0.27; 95% PrI, 0.11-0.62; SUCRA, 59.6%; low quality). CONCLUSIONS In a meta-analysis of data from 25 trials, we found rifaximin and lactulose to be most effective for reversal of minimal HE in patients with cirrhosis. L-ornithine L-aspartate and lactulose are most effective in the prevention of overt HE. Lactulose was the only agent that was effective in reversing minimal HE, preventing overt HE, reducing ammonia, and improving quality of life, with tolerable adverse effects. International prospective register of systematic reviews ID: 107003.
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Affiliation(s)
| | | | | | | | | | - Usha Dutta
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwani K Singal
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
| | | | | | - Meenu Singh
- Department of Paediatrics, Chandigarh, India
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Shiha G, Mousa N. Minimal Hepatic Encephalopathy: Silent Tragedy. LIVER DISEASE AND SURGERY [WORKING TITLE] 2019. [DOI: 10.5772/intechopen.88231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
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Critical flickering frequency test: a diagnostic tool for minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2019; 31:1030-1034. [PMID: 31274595 DOI: 10.1097/meg.0000000000001375] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Minimal hepatic encephalopathy (MHE) is underestimated. It affects 30-55% of patients with liver cirrhosis and can change their daily functions. Psychometric tests are sensitive in diagnosing MHE, but interpretation is difficult. Availability of a simpler diagnostic tool for MHE is mandatory. Critical flicker frequency (CFF) is a simple diagnostic test. AIM The aim of this study was to assess the diagnostic accuracy of CFF test for MHE. PATIENTS AND METHODS A total of 86 patients with cirrhosis with negative history of overt hepatic encephalopathy were included. History, clinical examination, laboratory investigations, and abdominal ultrasonography data were collected. Arabic version of number connection test, serial dotting test, and line tracing test were done. Total psychometric hepatic encephalopathy score (PHES) was used to diagnose MHE. CFF was done for all patients with MHE diagnosis at 39 Hz. RESULTS Of the 86 patients, 45 (52.3%) had MHE with PHES. Patients with MHE had significantly older age, presentation with jaundice, ascites, lower hemoglobin level, lower serum albumin, prolonged INR, higher Child class and score (P≤0.001), and higher model of end stage liver disease score (P=0.001) than patients without MHE. In comparison with PHES, CFF has a sensitivity of 91.1±8.32%, specificity of 92.7±7.96%, positive predictive value of 93.2±7.44%, and negative predictive value of 90.4±8.91%. In receiver operating characteristic curve, CFF is excellent in diagnosis of MHE, with area under the curve 0.937 (P<0.001). CONCLUSION MHE is common among patients with liver cirrhosis. CFF is a simple, rapid, noninvasive test for diagnosis of MHE, with a very good accuracy at 39 Hz.
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20
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Shen YC, Chang YH, Fang CJ, Lin YS. Zinc supplementation in patients with cirrhosis and hepatic encephalopathy: a systematic review and meta-analysis. Nutr J 2019; 18:34. [PMID: 31279342 PMCID: PMC6612144 DOI: 10.1186/s12937-019-0461-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 06/25/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Low serum zinc level is associated with hepatic encephalopathy (HE), but the efficacy of zinc supplementation remains uncertain. This study aimed to investigate the effects of zinc supplementation on HE treatment in patients with cirrhosis. METHODS We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (Cochrane CENTRAL) and Scopus from inception to December 2018; without publication date or language restrictions. Randomized controlled trials of zinc supplementation versus placebo or other treatment for the management of HE in adult patients with cirrhosis were selected. The primary outcome was the degree of HE as assessed by clinical signs or specialized psychometric tests. The secondary outcomes included serum ammonia levels, adverse events, or the length of hospital stay and costs. We carried out a meta-analysis with random effects model and summarized continuous outcomes using standardized mean differences (SMD) or mean differences (MD) with 95% confidence intervals (95% CI). The risk of bias was assessed using the Cochrane risk of bias tool, and the certainty of evidence for each outcome was evaluated with the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS Four trials with 247 patients were included. In patients with cirrhosis who had mild HE (≤ grade II), the available evidence suggested that the combination treatment of zinc supplementation and lactulose over 3 to 6 months significantly improved performance in the number connection test (SMD: -0.97; 95% CI: - 1.75 to - 0.19; P = 0.01; moderate certainty), reported in three trials (n = 227). However, compared with lactulose therapy alone, additional zinc supplementation demonstrated no significant difference in the digit symbol test (SMD: 0.44; 95% CI: - 0.12 to 1.00; P = 0.12; very low certainty) or serum ammonia levels (MD: -10.86; 95% CI: - 25.73 to 4.01; P = 0.15; very low certainty), reported in two trials (n = 137). None of the included trials reported adverse events or effects on hospitalization. CONCLUSIONS In conclusion, a combination of zinc supplementation and lactulose over 3 to 6 months may improve the number connection test in cirrhotic patients with low grade HE, compared with lactulose only. TRIAL REGISTRATION PROSPERO: CRD42017080955 . Registered 23 November 2017.
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Affiliation(s)
- Ying-Chi Shen
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Ya-Hui Chang
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
- Department of Pharmacy, MacKay Memorial Hospital, Taipei, Taiwan
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Ching-Ju Fang
- Medical Library, National Cheng Kung University, Tainan, Taiwan
- Department of Secretariat, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yang-Sheng Lin
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Evidence-Based Medicine Center, MacKay Memorial Hospital, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine and Deputy Director, Evidence-Based Medicine Center, MacKay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Zhongshan Dist., Taipei City, 104 Taiwan, Republic of China
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21
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González-Regueiro J, la Tijera MHD, Moreno-Alcántar R, Torre A. Pathophysiology of hepatic encephalopathy and future treatment options. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2019. [DOI: 10.1016/j.rgmxen.2019.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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22
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González-Regueiro JA, Higuera-de la Tijera MF, Moreno-Alcántar R, Torre A. Pathophysiology of hepatic encephalopathy and future treatment options. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2019; 84:195-203. [PMID: 31014748 DOI: 10.1016/j.rgmx.2019.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 01/28/2019] [Accepted: 02/18/2019] [Indexed: 06/09/2023]
Abstract
Understanding of the pathophysiology of hepatic encephalopathy has conditioned new treatment options. Ammonia detoxification in hepatic encephalopathy is regulated by two enzymes: glutaminase or glutamine synthetase. The first produces ammonia and the second detoxifies the ammonia, which is why treatments are aimed at glutaminase inhibition or glutamine synthetase activation. At present, we know that both enzymes are found not only in the liver, but also in the muscle, intestine, kidney, and brain. Therefore, current treatments can be directed at each enzyme at different sites. Awareness of those potential treatment sites makes different options of approach possible in the patient with hepatic encephalopathy, and each approach should be personalized.
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Affiliation(s)
- J A González-Regueiro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | | | - R Moreno-Alcántar
- Departamento de Gastroenterología, Centro Médico Nacional Siglo XXI, Ciudad de México, México
| | - A Torre
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México; Unidad de Hepatología y Trasplante Hepático, Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México.
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Montagnese S, Russo FP, Amodio P, Burra P, Gasbarrini A, Loguercio C, Marchesini G, Merli M, Ponziani FR, Riggio O, Scarpignato C. Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis 2019; 51:190-205. [PMID: 30606696 DOI: 10.1016/j.dld.2018.11.035] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/27/2018] [Accepted: 11/28/2018] [Indexed: 12/11/2022]
Abstract
Hepatic encephalopathy (HE) is a common, worrisome and sometimes difficult to manage complication of end-stage liver disease. HE is often recurrent, requiring multiple hospital admissions. It can have serious implications in terms of a patient's ability to perform complex tasks (for example driving), their earning capacity, their social and family roles. This guideline reviews current knowledge on HE definition, pathophysiology, diagnosis and treatment, both by general principles and by way of a summary of available drugs and treatment strategies. The quality of the published, pertinent evidence is graded, and practical recommendations are made. Where possible, these are placed within the Italian health service context, with reference to local diagnosis and management experience.
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Affiliation(s)
| | | | - Piero Amodio
- Department of Medicine, University of Padova, Italy
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy
| | - Antonio Gasbarrini
- Division of Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Carmela Loguercio
- Department of Clinical and Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Giulio Marchesini
- Unit of Metabolic Diseases & Clinical Dietetics, Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Manuela Merli
- Division of Gastroenterology, Department of Clinical Medicine, La Sapienza University of Rome, Italy
| | - Francesca Romana Ponziani
- Division of Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Oliviero Riggio
- Division of Gastroenterology, Department of Clinical Medicine, La Sapienza University of Rome, Italy
| | - Carmelo Scarpignato
- Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Italy
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Ridola L, Nardelli S, Gioia S, Riggio O. How to Design a Multicenter Clinical Trial in Hepatic Encephalopathy. J Clin Exp Hepatol 2019; 9:137-145. [PMID: 30765947 PMCID: PMC6363957 DOI: 10.1016/j.jceh.2018.02.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 02/20/2018] [Indexed: 12/12/2022] Open
Abstract
The design of clinical trials on Hepatic Encephalopathy (HE) is not an easy task, in fact there are several issues related to the performance of clinical trials in HE that have impeded progress in the field, mainly because most of the studies on HE therapy were performed before the era of rigorous Randomized Controlled Trials (RCTs). In this review we discuss the major problems affecting previously published trials on HE treatments aiming to provide evidences, suggestions and indications to prepare well designed RCTs in three different settings: (1) management of hospitalized patients with episodic HE; (2) secondary prophylaxis in patients following an episode of HE; and (3) management of minimal/covert HE.
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Affiliation(s)
- Lorenzo Ridola
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Italy
| | - Silvia Nardelli
- Department of Clinical Medicine, Sapienza University of Rome, Italy
| | - Stefania Gioia
- Department of Clinical Medicine, Sapienza University of Rome, Italy
| | - Oliviero Riggio
- Department of Clinical Medicine, Sapienza University of Rome, Italy
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Affiliation(s)
- Chathur Acharya
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
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Butterworth RF, Kircheis G, Hilger N, McPhail MJ. Efficacy of l-Ornithine l-Aspartate for the Treatment of Hepatic Encephalopathy and Hyperammonemia in Cirrhosis: Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Clin Exp Hepatol 2018; 8:301-313. [PMID: 30302048 PMCID: PMC6175748 DOI: 10.1016/j.jceh.2018.05.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/08/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVES l-Ornithine l-Aspartate (LOLA) is a mixture of two endogenous amino acids with the capacity to fix ammonia in the form of urea and/or glutamine. Its' efficacy for the treatment of Hepatic Encephalopathy (HE), a known hyperammonemic disorder, remains the subject of debate. This study quantitatively analyzed the efficacy of LOLA in patients with cirrhosis and HE. METHODS Efficacy was defined as the extent of lowering of blood ammonia and improvement of mental state assessed in clinically overt HE (OHE) by Westhaven criteria or psychometric testing for assessment of Minimal HE (MHE). Appropriate keywords were used for electronic and/or manual searches of databases to identify RCTs for inclusion. Study quality and risk of bias were assessed using the Jadad Composite Scale together with The Cochrane Scoring Tool. Random Effects Models were used to express pooled Risk Ratio (RR) or Mean Difference (MD) with associated 95% Confidence Intervals (CI). RESULTS 10 RCTs (884 patients) were included. Regression analysis showed no evidence of publication bias or other small study effects. Eight RCTs had low risk of bias by Jadad/Cochrane criteria. Comparison with placebo/no intervention controls revealed that LOLA was significantly more effective for improvement of mental state in all types of HE (RR 1.36 (95% CI 1.10-1.69), p = 0.005), OHE (RR: 1.19, 95% CI of 1.01-1.39, test for overall effect: Z = 2.14, p = 0.03), MHE (RR: 2.15 (1.48-3.14), p < 0.0001) and for lowering of blood ammonia (MD: -17.50 μmol/l (-27.73 to (-7.26)), p = 0.0008). Improvement of mental state was greater in trials with low risk of bias. Heterogeneity was reduced in trials from Europe or with >100 participants. Oral LOLA appeared particularly effective for the treatment of MHE. CONCLUSION LOLA appears to improve mental state and lower ammonia in patients with HE or MHE. Further studies are required in some subgroups of HE and in the era of HE reclassification.
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Affiliation(s)
| | - Gerald Kircheis
- Clinic of Brandenburg, Medical University Brandenburg Theodor Fontane, Germany
| | - Norbert Hilger
- Institute of Psychology, Methodology, Diagnostics and Evaluations, University of Bonn, Germany
| | - Mark J.W. McPhail
- Liver Intensive Therapy Unit, Institute of Liver Sciences, Division of Inflammation Biology, School of Immunology and Microbial Sciences, Kings College London, United Kingdom
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Ridola L, Cardinale V, Riggio O. The burden of minimal hepatic encephalopathy: from diagnosis to therapeutic strategies. Ann Gastroenterol 2018; 31:151-164. [PMID: 29507462 PMCID: PMC5825945 DOI: 10.20524/aog.2018.0232] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 11/29/2017] [Indexed: 12/12/2022] Open
Abstract
Minimal hepatic encephalopathy (MHE) is the mildest form of hepatic encephalopathy (HE). It affects the performance of psychometric tests focused on attention, working memory, psychomotor speed, and visuospatial ability, as well as electrophysiological and other functional brain measures. MHE is a frequent complication of liver disease, affecting up to 80% of tested patients. By being related to falls, an impairment in fitness to drive and the development of overt HE, MHE severely affects the lives of patients and caregivers by altering their quality of life and their socioeconomic status. MHE is detected in clinically asymptomatic patients using appropriate psychometric tests and neurophysiological methods that highlight neuropsychological alterations, such as video-spatial orientation deficits, attention disorders, memory, reaction times, electroencephalogram slowing, prolongation of latency-evoked cognitive potentials, and reduction in the critical flicker frequency. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics such as rifaximin, probiotics and branched-chain amino acids. However, because of the multiple diagnosis methods, the various endpoints of treatment trials and the variety of agents used in trials, the treatment of MHE is not currently recommended as routine, but only on a case-by-case basis.
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Affiliation(s)
- Lorenzo Ridola
- Department of Medico-Surgical Sciences and Biotechnologies (Lorenzo Ridola, Vincenzo Cardinale), Sapienza University of Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies (Lorenzo Ridola, Vincenzo Cardinale), Sapienza University of Rome, Italy
| | - Oliviero Riggio
- Department of Clinical Medicine (Oliviero Riggio), Sapienza University of Rome, Italy
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The Effects of Probiotics and Symbiotics on Risk Factors for Hepatic Encephalopathy: A Systematic Review. J Clin Gastroenterol 2017; 51:312-323. [PMID: 28059938 DOI: 10.1097/mcg.0000000000000789] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alterations in the levels of intestinal microbiota, endotoxemia, and inflammation are novel areas of interest in the pathogenesis of hepatic encephalopathy (HE). Probiotics and symbiotics are a promising treatment option for HE due to possible beneficial effects in modulating gut microflora and might be better tolerated and more cost-effective than the traditional treatment with lactulose, rifaximin or L-ornithine-L-aspartate. A systematic search of the electronic databases PubMed, ISI Web of Science, EMBASE, and Cochrane Library was conducted for randomized controlled clinical trials in adult patients with cirrhosis, evaluating the effect of probiotics and symbiotics in changes on intestinal microflora, reduction of endotoxemia, inflammation, and ammonia, reversal of minimal hepatic encephalopathy (MHE), prevention of overt hepatic encephalopathy (OHE), and improvement of quality of life. Nineteen trials met the inclusion criteria. Probiotics and symbiotics increased beneficial microflora and decreased pathogenic bacteria and endotoxemia compared with placebo/no treatment, but no effect was observed on inflammation. Probiotics significantly reversed MHE [risk ratio, 1.53; 95% confidence interval (CI): 1.14, 2.05; P=0.005] and reduced OHE development (risk ratio, 0.62; 95% CI: 0.48, 0.80; P=0.0002) compared with placebo/no treatment. Symbiotics significantly decreased ammonia levels compared with placebo (15.24; 95% CI: -26.01, -4.47; P=0.006). Probiotics did not show any additional benefit on reversal of MHE and prevention of OHE development when compared with lactulose, rifaximin, and L-ornithine-L-aspartate. Only 5 trials considered tolerance with minimal side effects reported. Although further research is warranted, probiotics and symbiotics should be considered as an alternative therapy for the treatment and management of HE given the results reported in this systematic review.
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Montagnese S, De Rui M, Angeli P, Amodio P. Neuropsychiatric performance in patients with cirrhosis: Who is "normal"? J Hepatol 2017; 66:825-835. [PMID: 27923694 DOI: 10.1016/j.jhep.2016.11.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 11/24/2016] [Accepted: 11/24/2016] [Indexed: 02/08/2023]
Abstract
In patients with cirrhosis a normal neuropsychiatric performance has been traditionally defined by the absence of any degree of hepatic encephalopathy and/or the absence of psychometric or neurophysiological abnormalities, compared with data from the healthy population. As the understanding and management of end-stage liver disease continues to change, it is our impression that the concept of normal neuropsychiatric performance also needs updating. This review explores novel and more pragmatic interpretations of neuropsychiatric "normality" compared with top personal performance, in terms of risk of overt hepatic encephalopathy or brain failure and in relation with events such as liver transplantation, decompensation, acute-on-chronic liver failure and transjugular intrahepatic portosystemic shunt placement.
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Affiliation(s)
| | - Michele De Rui
- Department of Medicine, University of Padua, Padua, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padua, Padua, Italy
| | - Piero Amodio
- Department of Medicine, University of Padua, Padua, Italy
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El-Karaksy HM, Afifi O, Bakry A, Kader AA, Saber N. A pilot study using lactulose in management of minimal hepatic encephalopathy in children with extrahepatic portal vein obstruction. World J Pediatr 2017; 13:70-75. [PMID: 27878780 DOI: 10.1007/s12519-016-0066-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 04/20/2015] [Indexed: 12/30/2022]
Abstract
BACKGROUND Minimal hepatic encephalopathy (MHE) is not associated with overt neuropsychiatric symptoms but rather with subtle changes in psychometric and/or neurophysiologic tests. We aimed to diagnose MHE in children with extrahepatic portal vein obstruction (EHPVO) and to evaluate the effect of lactulose on MHE. METHODS A prospective study was carried out on 30 patients with EHPVO (21 males; mean age 10±2.5 years). The study was carried out in the Pediatric Hepatology Unit, Cairo University Pediatric Hospital, Cairo, Egypt, between 2011 and 2013. All patients were subjected to clinical and laboratory assessment, neuropsychmetric testing using the arabic version of Wechsler intelligence tests, neurophysiological testing by visual electroencephalogram and P300 event related potentials (ERP). RESULTS The prevalence of MHE among children with EHPVO was 20% (6/30). After randomization to treatment and no-treatment groups using lactulose, all tests were repeated after three months. Among four patients with MHE who received lactulose, three (75%) improved. On the other hand, one of the patients in the no-treatment group developed MHE. Only one patient in the treatment arm had to discontinue lactulose because of severe diarrhea. CONCLUSIONS This pilot study revealed that the prevalence of MHE was 20%. Improvement on psychometic tests was seen in 75% of our patients (3/4) after treatment with lactulose. Lactulose treatment was well tolerated.
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Affiliation(s)
- Hanaa Mostafa El-Karaksy
- Department of Pediatrics, Kasr Alainy School of Medicine, Cairo University, Giza, Egypt.
- , 44 Mohei El-Deen Abu El-Ezz Street, Dokki, Cairo, 12311, Egypt.
| | - Omneya Afifi
- Department of Pediatrics, Kasr Alainy School of Medicine, Cairo University, Giza, Egypt
| | - Azza Bakry
- Department of Psychiatry, Kasr Alainy School of Medicine, Cairo University, Giza, Egypt
| | - Ann Abdel Kader
- Department of Neurophysiology, Kasr Alainy School of Medicine, Cairo University, Giza, Egypt
| | - Noha Saber
- Department of Psychiatry, Kasr Alainy School of Medicine, Cairo University, Giza, Egypt
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Soisangwan N, Khuwijitjaru P, Kobayashi T, Adachi S. Kinetic Analysis of Lactulose Production from Lactose in Subcritical Aqueous Ethanol. FOOD SCIENCE AND TECHNOLOGY RESEARCH 2017. [DOI: 10.3136/fstr.23.45] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Nontanut Soisangwan
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University
- Department of Biotechnology, Faculty of Agro-Industry, Kasetsart University
| | - Pramote Khuwijitjaru
- Department of Food Technology, Faculty of Engineering and Industrial Technology, Silpakorn University
| | - Takashi Kobayashi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University
| | - Shuji Adachi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University
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Abstract
INTRODUCTION Minimal hepatic encephalopathy (MHE) can reverse after short-term treatment. However, relapse rate of MHE after stopping treatment has not been studied so far. We aimed to evaluate long-term (9 months) efficacy of a short-term (3 months) treatment of MHE with lactulose/rifaximin, for maintenance of remission from MHE. MATERIAL AND METHODS In this prospective study, consecutive patients with cirrhosis and MHE were treated with lactulose/rifaximin for 3 months. After treatment, they were followed up for 6 months. Psychometric testing for diagnosis of MHE was performed at baseline, 3 months and 9 months. RESULTS Of the 527 patients screened, 351 were found eligible and tested for MHE. Out of these, 112 (31.9%) patients had MHE (mean age 55.3 years; 75% males). They were randomized to receive Rifaximin (n = 57; 1,200 mg/day) or Lactulose (n = 55; 30-120 mL/day) for three months. At 3 months, 73.7% (42/57) patients in Rifaximin group experienced MHE reversal compared to 69.1% (38/55) in Lactulose group (p = 0.677). Six months after stopping treatment, 47.6% (20/42) in rifaximin group and 42.1% (16/38) patients in lactulose group experienced MHE relapse (p = 0.274). The overt hepatic encephalopathy development rate (7.1% vs. 7.9%) and mortality rate (0.23% vs. 0%) were similar in both groups. The Child-Turcotte-Pugh score and model for end stage liver disease (MELD) scores of patients who had MHE relapse were higher compared to those who didn't. On multivariate regression analysis, MELD score was an independent predictor of MHE relapse. CONCLUSION Of the patients who became MHE negative after short-term (3 months) treatment with rifaximin/lactulose, almost 50% had a relapse of MHE at 6 months follow-up.
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Affiliation(s)
- Omesh Goyal
- Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Sandeep S Sidhu
- Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Harsh Kishore
- Dayanand Medical College and Hospital, Ludhiana, Punjab, India
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De Rui M, Montagnese S, Amodio P. Recent developments in the diagnosis and treatment of covert/minimal hepatic encephalopathy. Expert Rev Gastroenterol Hepatol 2016; 10:443-50. [PMID: 26758861 DOI: 10.1586/17474124.2016.1141675] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The terms minimal hepatic encephalopathy and covert hepatic encephalopathy are defined. Clinical assessment is unreliable and both require the use of diagnostic tools. Of these, psychometric tests are the most widely used. They require proper standardization and may be biased by patient cooperation or lack thereof. The measure of the critical flicker frequency and of the electroencephalogram, possibly quantified, are also useful. The alteration of any of them is not strictly parallel in size and may vary from patient to patient. When possible, the use of multiple measures might increase diagnostic reliability. These functional measures should be interpreted within the clinical/biochemical profile of the patient to exclude other disorders. A flow chart for treatment is proposed on the basis of current knowledge.
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Affiliation(s)
- M De Rui
- a Department of Medicine , University of Padua , Padua , Italy
| | - S Montagnese
- a Department of Medicine , University of Padua , Padua , Italy
| | - P Amodio
- a Department of Medicine , University of Padua , Padua , Italy
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Soisangwan N, Gao DM, Kobayashi T, Khuwijitjaru P, Adachi S. Kinetic analysis for the isomerization of cellobiose to cellobiulose in subcritical aqueous ethanol. Carbohydr Res 2016; 433:67-72. [DOI: 10.1016/j.carres.2016.07.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 07/08/2016] [Accepted: 07/09/2016] [Indexed: 12/22/2022]
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Gluud LL, Vilstrup H, Morgan MY. Nonabsorbable disaccharides for hepatic encephalopathy: A systematic review and meta-analysis. Hepatology 2016; 64:908-22. [PMID: 27081787 DOI: 10.1002/hep.28598] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 03/25/2016] [Accepted: 04/04/2016] [Indexed: 12/21/2022]
Abstract
UNLABELLED Nonabsorbable disaccharides (NADs) have been used to treat hepatic encephalopathy (HE) since 1966. However, a Cochrane Review, published in 2004, found insufficient evidence to recommend their use in this context. This updated systematic review evaluates the effects of the NADs, lactulose and lactitol, for the treatment and prevention of HE in patients with cirrhosis. Thirty-eight randomized controlled trials, involving 1,828 patients, were identified through electronic and manual searches; 31 randomized controlled trials looked at the treatment of HE, while seven looked at its primary/secondary prevention. Random-effects meta-analyses showed that, compared to placebo/no intervention, NADs had a beneficial effect on HE (relative risk [RR] = 0.63, 95% confidence interval [CI] 0.53-0.74, number needed to treat [NNT] = 4) and serious liver-related adverse events such as liver failure, variceal bleeding, serious infections, spontaneous bacterial peritonitis, and hepatorenal syndrome (RR = 0.42, 95% CI 0.26-0.69, NNT = 50). Treatment was also associated with a reduction in mortality in patients with overt HE (RR = 0.36, 95% CI 0.14-0.94, NNT = 20), although not in patients with minimal HE. Meta-analyses of the prevention randomized controlled trials showed that NADs prevented the development of HE (RR = 0.47, 95% CI 0.33-0.68, NNT = 6), the risk of developing serious liver-related adverse events (RR = 0.48, 95% CI 0.33-0.70, NNT = 6), and reduced mortality (RR = 0.63, 95% CI 0.40-0.98, NNT = 20). Use of NADs was associated with nonserious gastrointestinal adverse events. There were no differences in the efficacy or safety of lactulose and lactitol. CONCLUSIONS NADs have beneficial effects in the treatment and prevention of HE; their use, in this context, confers additional benefits including a reduction in serious liver-related morbidities and all-cause mortality. (Hepatology 2016;64:908-922).
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Affiliation(s)
- Lise L Gluud
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, 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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Sweigart JR, Bradley B, Grigorian AY. Hepatic encephalopathy for the hospitalist. J Hosp Med 2016; 11:591-4. [PMID: 26949923 DOI: 10.1002/jhm.2579] [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] [Received: 08/07/2015] [Revised: 02/01/2016] [Accepted: 02/13/2016] [Indexed: 11/12/2022]
Abstract
The care of patients with advanced liver disease is often complicated by episodes of acute decline in alertness and cognition, termed hepatic encephalopathy (HE). Hospitalists must be familiar with HE, as it is a common reason for hospitalization in this population and is associated with significantly increased mortality. This narrative review addresses common issues related to diagnosis and classification, precipitants, inpatient management, and transitions of care for patients with HE. The initial presentation can be variable, and HE remains a clinical diagnosis. The spectrum of HE manifestations spans from mild, subclinical cognitive deficits to overt coma. The West Haven scoring system is the most widely used classification system for HE. Various metabolic insults may precipitate HE, and providers must specifically seek to rule out infection and bleeding in cirrhotic patients presenting with altered cognition. This is consistent with the 4-pronged approach of the American Association for the Study of Liver Disease practice guidelines. Patients with HE are typically treated primarily with nonabsorbable disaccharide laxatives, often with adjunctive rifaximin. The evidence for these agents is discussed, and available support for other treatment options is presented. Management issues relevant to general hospitalists include those related to acute pain management, decisional capacity, and HE following transjugular intrahepatic portosystemic shunt placement. These issues are examined individually. Successfully transitioning patients recovering from HE to outpatient care requires open communication with multiple role players including patients, caregivers, and outpatient providers. Journal of Hospital Medicine 2016;11:591-594. © 2016 Society of Hospital Medicine.
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Affiliation(s)
- Joseph R Sweigart
- Division of Hospital Medicine, University of Kentucky, Lexington, Kentucky
| | - Bruce Bradley
- Division of Hospital Medicine, University of Kentucky, Lexington, Kentucky
| | - Alla Y Grigorian
- Division of Gastroenterology, University of Kentucky, Lexington, Kentucky
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Zhang Y, Feng Y, Cao B, Tian Q. The effect of small intestinal bacterial overgrowth on minimal hepatic encephalopathy in patients with cirrhosis. Arch Med Sci 2016; 12:592-6. [PMID: 27279853 PMCID: PMC4889679 DOI: 10.5114/aoms.2015.55675] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 11/18/2013] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION The aim of the study was to investigate the significance of factors associated with minimal hepatic encephalopathy (MHE) in cirrhotic patients. MATERIAL AND METHODS Between September 2012 and August 2013, 60 cirrhotic patients, including MHE and non-MHE (NMHE) patients, were included in the study. Associated factors and clinical factors were analyzed to see if they were significantly different between MHE and non-MHE patients. Upon identifying the factors showing differences, we applied multivariate regression analysis to further decide which were the most significant ones to differentiate MHE from NMHE patients. RESULTS There were 26 patients diagnosed with MHE and 34 with NMHE. Our results demonstrated that the prevalence rate of small intestinal bacterial overgrowth (SIBO) was highly associated with patients with MHE (65.4%, 17 out of 26), in contrast to the rate in NMHE patients (8.8%, 3 out of 34). We also found that factors including age, education level, intelligent test results, plasma albumin level and plasma ammonia levels were significantly different between MHE and NMHE patients. Ultimately, with logistic regression analysis, we found that SIBO was the most significant factor differentiating MHE patients from NMHE patients (p < 0.05). CONCLUSIONS In cirrhotic patients, SIBO was highly associated with MHE. This may further our understanding of the mechanisms of MHE and help to develop potential therapeutic interventions to treat cirrhotic patients with MHE.
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Affiliation(s)
- Yuying Zhang
- Department of Gastroenterology, Wei Fang People's Hospital, Weifang, Shan Dong, China
| | - Yikuan Feng
- Department of Gastroenterology, Wei Fang People's Hospital, Weifang, Shan Dong, China
| | - Bin Cao
- Department of Gastroenterology, Wei Fang People's Hospital, Weifang, Shan Dong, China
- Affiliated Hospital, Medical College, Qingdao University, Qingdao, China
| | - Qiang Tian
- Department of Gastroenterology, Wei Fang People's Hospital, Weifang, Shan Dong, China
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Soisangwan N, Gao DM, Kobayashi T, Khuwijitjaru P, Adachi S. Production of Lactulose from Lactose in Subcritical Aqueous Ethanol. J FOOD PROCESS ENG 2016. [DOI: 10.1111/jfpe.12413] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Nontanut Soisangwan
- Division of Food Science and Biotechnology, Graduate School of Agriculture; Kyoto University; Sakyo-ku Kyoto 606-8502 Japan
- Department of Biotechnology, Faculty of Agro-Industry; Kasetsart University; Bangkok 10900 Thailand
| | - Da-Ming Gao
- Division of Food Science and Biotechnology, Graduate School of Agriculture; Kyoto University; Sakyo-ku Kyoto 606-8502 Japan
| | - Takashi Kobayashi
- Division of Food Science and Biotechnology, Graduate School of Agriculture; Kyoto University; Sakyo-ku Kyoto 606-8502 Japan
| | - Pramote Khuwijitjaru
- Division of Food Science and Biotechnology, Graduate School of Agriculture; Kyoto University; Sakyo-ku Kyoto 606-8502 Japan
- Department of Food Technology, Faculty of Engineering and Industrial Technology; Silpakorn University; Nakhon Pathom 73000 Thailand
| | - Shuji Adachi
- Division of Food Science and Biotechnology, Graduate School of Agriculture; Kyoto University; Sakyo-ku Kyoto 606-8502 Japan
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Gluud LL, Vilstrup H, Morgan MY, Cochrane Hepato‐Biliary Group. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2016; 2016:CD003044. [PMID: 27153247 PMCID: PMC7004252 DOI: 10.1002/14651858.cd003044.pub4] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Non-absorbable disaccharides (lactulose and lactitol) are recommended as first-line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 randomised clinical trials (RCTs) evaluating non-absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non-absorbable disaccharides and no differences between lactulose versus lactitol. OBJECTIVES To assess the beneficial and harmful effects of i) non-absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy. SEARCH METHODS We carried out electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies. SELECTION CRITERIA We included RCTs, irrespective of publication status, language, or blinding. DATA COLLECTION AND ANALYSIS Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta-analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato-Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses. MAIN RESULTS We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random-effects meta-analysis showed a beneficial effect of non-absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non-absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I(2) = 32%; moderate quality evidence). Additional analyses showed that non-absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non-absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta-analysis (very low quality evidence). Non-absorbable disaccharides were associated with non-serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence). AUTHORS' CONCLUSIONS This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non-absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.
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Affiliation(s)
- Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionKettegaards AlleHvidovreDenmark2650
| | - Hendrik Vilstrup
- Aarhus KommunehospitalDepartment of Hepatology and GastroenterologyNørrebrogade 44Aarhus CDenmarkDK‐8000
| | - Marsha Y Morgan
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthRowland Hill StreetHampsteadLondonUKNW3 2PF
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Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2016; 4:CD003044. [PMID: 27089005 DOI: 10.1002/14651858.cd003044.pub3] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Non-absorbable disaccharides (lactulose and lactitol) are recommended as first-line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 randomised clinical trials (RCTs) evaluating non-absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non-absorbable disaccharides and no differences between lactulose versus lactitol. OBJECTIVES To assess the beneficial and harmful effects of i) non-absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy. SEARCH METHODS We carried out electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies. SELECTION CRITERIA We included RCTs, irrespective of publication status, language, or blinding. DATA COLLECTION AND ANALYSIS Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta-analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato-Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses. MAIN RESULTS We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random-effects meta-analysis showed a beneficial effect of non-absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non-absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I(2) = 32%; moderate quality evidence). Additional analyses showed that non-absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non-absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta-analysis (very low quality evidence). Non-absorbable disaccharides were associated with non-serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence). AUTHORS' CONCLUSIONS This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non-absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.
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Affiliation(s)
- Lise Lotte Gluud
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Kettegaards Alle, Hvidovre, Denmark, 2650
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Maharshi S, Sharma BC, Sachdeva S, Srivastava S, Sharma P. Efficacy of Nutritional Therapy for Patients With Cirrhosis and Minimal Hepatic Encephalopathy in a Randomized Trial. Clin Gastroenterol Hepatol 2016; 14:454-460.e3; quiz e33. [PMID: 26453952 DOI: 10.1016/j.cgh.2015.09.028] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 09/18/2015] [Accepted: 09/29/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Minimal hepatic encephalopathy (MHE) impairs health-related quality of life (HRQOL), leads to the development of overt HE, and is associated with poor outcome. We performed a randomized controlled trial to assess the effects of nutritional therapy on cognitive functions and HRQOL in patients with cirrhosis with MHE. METHODS In a tertiary care setting in New Delhi, India, patients with cirrhosis with MHE were assigned randomly to groups given nutritional therapy (30-35 kcal/kg/d, 1.0-1.5 g vegetable protein/kg/d; n = 60; age, 42.1 ± 10.3 y; 48 men) or no nutritional therapy (patients continued on their same diet; n = 60; age, 42.4 ± 9.6 y; 47 men) for 6 months in 2014. MHE was diagnosed based on their psychometry hepatic encephalopathy score (PHES). HRQOL was assessed by a sickness impact profile (SIP) questionnaire. Primary end points were improvement or worsening in MHE and improvement in HRQOL. RESULTS There was no significant difference in baseline PHES (-8.12 ± 1.32 vs -8.53 ± 1.38; P = .08) or SIP (14.25 ± 5.8 vs 15.44 ± 5.03; P = .85) scores. After the 6-month study period, a higher proportion of patients in the nutritional therapy group had reversal of MHE (71.1% vs 22.8%; P = .001). Patients in the nutritional therapy group also had larger increases in PHES (3.86 ± 3.58 vs 0.52 ± 4.09; P = .001) and HRQOL (improvement in SIP score of 3.24 ± 3.63 vs 0.54 ± 3.58; P = .001). Overt HE developed in 10% of patients in the nutritional therapy group vs 21.7% of the control group (P = .04). CONCLUSIONS Based on a randomized controlled trial performed in India, nutritional therapy is effective in the treatment of MHE and is associated with improvement in HRQOL. Clinical Trial Registry-India registration no: CTRI/2013/07/003851.
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Affiliation(s)
- Sudhir Maharshi
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | | | - Sanjeev Sachdeva
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | | | - Praveen Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
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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: 148] [Impact Index Per Article: 14.8] [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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Clinical and pathophysiological consequences of alterations in the microbiome in cirrhosis. Am J Gastroenterol 2015; 110:1399-410; quiz 1411. [PMID: 26416191 DOI: 10.1038/ajg.2015.313] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 08/04/2015] [Indexed: 02/06/2023]
Abstract
Cirrhosis is a major cause of mortality worldwide. Exponential rises in prevalence have been observed secondary to increases in obesity and alcohol consumption. Multiple lines of evidence implicate gut-derived bacteria and bacterial ligands as a central driver of pathogenesis. Recent developments in culture-independent techniques have facilitated a more accurate description of microbiome composition in cirrhosis and led to the description of measures of dysbiosis shown to be associated with disease. More importantly, metagenomic studies are adding to an understanding of the functional contribution of the microbiota and may prove to be a more clinically relevant biomarker than phylogenetic studies. Much like other dysbiotic states such as inflammatory bowel disease, the microbiota in cirrhosis is characterized by a low microbial and genetic diversity. Therapeutic strategies to diminish this process are currently limited to selective intestinal decontamination with antibiotics. This review summarizes the available data and develops a framework for the use of current and future treatment strategies to diminish the consequences of dysbiosis in cirrhosis. Interventional strategies to bind bacterial products in the gut lumen and blood, and modulate the magnitude of host sensing mechanisms remain an unmet clinical need. A greater understanding of the host-microbiota interaction in cirrhosis is of key importance to inform future interventional strategies to diminish the currently escalating burden of the disease.
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Pratap Mouli V, Benjamin J, Bhushan Singh M, Mani K, Garg SK, Saraya A, Joshi YK. Effect of probiotic VSL#3 in the treatment of minimal hepatic encephalopathy: A non-inferiority randomized controlled trial. Hepatol Res 2015; 45:880-9. [PMID: 25266207 DOI: 10.1111/hepr.12429] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 09/13/2014] [Accepted: 09/25/2014] [Indexed: 02/07/2023]
Abstract
AIM Minimal hepatic encephalopathy (MHE) impairs daily functioning and health-related quality of life in chronic liver disease (CLD). Lactulose is the standard treatment but has side-effects. Probiotics have an encouraging role in MHE. The aim of the present study was to test whether probiotics are non-inferior to lactulose in improving MHE. METHODS Patients with CLD (n = 227) were screened for MHE using neuropsychometric tests (number connection tests A and B [or figure connection tests A and B]) and/or neurophysiological test (P-300 auditory event-related potential), and 120 (53%) were diagnosed with MHE by abnormal tests. MHE patients were randomized to lactulose (30-60 mL/day) or probiotic (four capsules of VSL#3; total of 450 billion CFU/day) for 2 months. Response was defined as normalization of tests. Serum ammonia was measured by commercial kit. RESULTS Of 120 patients randomized, 40 in the lactulose arm and 33 in the probiotic arm completed 2 months of intervention. MHE improved in 25 (62.5%) patients taking lactulose and 23 (69.7%) taking probiotics. The effect size of difference of improvement in MHE between lactulose and probiotic was 0.072 per per-protocol analysis and 0.040 as per intention to treat analysis (within -20% of non-inferiority margin). Serum ammonia was comparable between groups at baseline and 2 months; it decreased in patients in whom MHE improved, while increased in patients with no improvement in MHE. CONCLUSION The probiotic VSL#3 was non-inferior to the standard therapy, lactulose in the treatment of MHE. Improvement in MHE correlated with reduction of ammonia levels.
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Affiliation(s)
- Venigalla Pratap Mouli
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Jaya Benjamin
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Mamta Bhushan Singh
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Kalaivani Mani
- Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Sushil Kumar Garg
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Yogendra Kumar Joshi
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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Abstract
Hepatic encephalopathy exists along a continuum from abnormal neuropsychiatric testing in the absence of clinical findings to varying degrees of detectable clinical findings. The International Society for Hepatic Encephalopathy and Nitrogen Metabolism has endorsed the term "covert" to encompass minimal hepatic encephalopathy and grade I overt hepatic encephalopathy. Covert hepatic encephalopathy has been associated with poor quality of life, decreased employment, increased falls, and increased traffic accidents that significantly impact quality of life and health care expenditures. Probiotics, nonabsorbable dissacharides, rifaximin, and l-ornithine-l-aspartate have been evaluated with varying levels of success. Because of the lack of universally accepted diagnostic tools, optimal timing of testing and treatment remains controversial.
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Affiliation(s)
- Phillip K Henderson
- Division of Gastroenterology, University of South Alabama, 6000 University Commons, 75 University Boulevard South, Mobile, AL 36688, USA
| | - Jorge L Herrera
- Division of Hepatology, University of South Alabama, 6000 University Commons, 75 University Boulevard South, Mobile, AL 36688, USA.
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Agrawal S, Umapathy S, Dhiman RK. Minimal hepatic encephalopathy impairs quality of life. J Clin Exp Hepatol 2015; 5:S42-8. [PMID: 26041957 PMCID: PMC4442849 DOI: 10.1016/j.jceh.2014.11.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 11/26/2014] [Indexed: 01/18/2023] Open
Abstract
Minimal hepatic encephalopathy (MHE) is the mildest form of the spectrum of neurocognitive impairment in cirrhosis. It is a frequent occurrence in patients of cirrhosis and is detectable only by specialized neurocognitive testing. MHE is a clinically significant disorder which impairs daily functioning, driving performance, work capability and learning ability. It also predisposes to the development of overt hepatic encephalopathy, increased falls and increased mortality. This results in impaired quality of life for the patient as well as significant social and economic burden for health providers and care givers. Early detection and treatment of MHE with ammonia lowering therapy can reverse MHE and improve quality of life.
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Affiliation(s)
| | | | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India
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Waghray A, Waghray N, Mullen K. Management of covert hepatic encephalopathy. J Clin Exp Hepatol 2015; 5:S75-81. [PMID: 26041963 PMCID: PMC4442854 DOI: 10.1016/j.jceh.2014.02.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 02/19/2014] [Indexed: 02/07/2023] Open
Abstract
Hepatic encephalopathy is a reversible progressive neuropsychiatric disorder that encompasses a wide clinical spectrum. Covert hepatic encephalopathy is defined as patients with minimal hepatic encephalopathy and Grade I encephalopathy by West-Haven Criteria. Terminology such as "sub-clinical", "latent", and "minimal" appear to trivialize the disease and have been replaced by the term covert. The lack of clinical signs means that covert hepatic encephalopathy is rarely recognized or treated outside of clinical trials with options for therapy based on patients with episodic hepatic encephalopathy. This review discusses the current available options for therapy in covert hepatic encephalopathy and focuses on non-absorbable disacharides (lactulose or lactitol), antibiotics (rifaximin), probiotics/synbiotics and l-ornithine-l-aspartate.
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Key Words
- APT, abnormal psychometric testing
- BAEP, brain auditory evoked potential
- BDT, block design test
- CFF, critical flicker frequency
- DST, digit symbol test
- FCT-A, Figure connection test-A
- FOS, fructo-oligosaccharides
- HRQoL, health-related quality of life
- ICT, inhibitory control test
- LCT, line tracing test
- NCT-A, number connection tests A
- NCT-B, number connection tests B
- NPE, neuropsychological exam
- OCTT, orocecal transit time
- PCT, Picture completion test
- PSE, psychometric testing
- RCT, race track test
- SDMT, Symbol digit modalities test
- SDT, serial-dotting test
- SPT, standard psychometric test
- TMT, Trail making test
- hepatic encephalopathy
- lactulose
- probiotics
- rifaximin
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Affiliation(s)
- Abhijeet Waghray
- Department of Medicine, MetroHealth Medical Center/Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA
| | - Nisheet Waghray
- Division of Gastroenterology, MetroHealth Medical Center/Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA
| | - Kevin Mullen
- Division of Gastroenterology, MetroHealth Medical Center/Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA
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Sharma M, Bhat S, Dutt K, Sharma P, Bhat JA. RANDOMIZED CONTROLLED TRIAL OF LACTULOSE AND LACTULOSE PLUS PROBIOTICS IN THE TREATMENT OF MINIMAL HEPATIC ENCEPHALOPATHY. ACTA ACUST UNITED AC 2014. [DOI: 10.18410/jebmh/2014/166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Yao C, Huang G, Wang M, Xia M, Yao F, Niu D, Zhang Y, Li S, Zhong Y. Chinese herbal medicine formula Jieduhuayu granules improves cognitive and neurophysiological functions in patients with cirrhosis who have minimal hepatic encephalopathy: a randomized controlled trial. Complement Ther Med 2014; 22:977-85. [PMID: 25453517 DOI: 10.1016/j.ctim.2014.10.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 09/17/2014] [Accepted: 10/03/2014] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Minimal hepatic encephalopathy (MHE) impairs patients' cognitive and neurophysiological functions. In this study, we investigated the effect of treatment-related improvement in cognitive and neurophysiological functions. METHODS We measured psychometric performance by number connection tests part A (NCT-A), digit symbol test (DST), mini-mental state examination (MMSE) and event related potential P300 wave of 80 patients with cirrhosis who have minimal hepatic encephalopathy on inclusion into the study and 15 days later. They were randomly assigned in a 1:1:1:1 ratio to four groups, to receive treatment of Chinese herbal medicine formula (HMG) or lactulose (LG) or Chinese herbal medicine formula combined with lactulose (HMCLG) for 15 days (n=20) or no treatment (CG) (n=20). This study was not blind. RESULTS The mean number of NCT-A and MMSE scores improved significantly in patients in the HMG (0 day, 102.00±24.49 for NCT-A, 18.55±2.89 for MMSE; 15 days, 78.30±22.55 for NCT-A, 24.20±2.78 for MMSE) compared with patients in the CG after 15 days of follow-up (0 day, 103.00±24.98 for NCT-A, 17.90±2.99 for MMSE; 15 days, 95.65±24.34 for NCT-A, 18.85±3.12 for MMSE), P<0.05; the mean number of P300 latency (ms) and wave amplitude (μV) improved significantly among patients in the HMG after 15 days of treatment (0 day, 341.90±14.04 for latency, 8.40±1.73 for wave amplitude; 15 days, 305.45±23.95 for latency, 13.00±3.80 for wave amplitude) compared with patients in the CG after 15 days of follow-up (0 day, 343.85±14.88 for latency, 8.29±1.77 for wave amplitude; 15 days, 340.40±13.06 for latency, 8.50±1.82 for wave amplitude), P<0.05. Similar improvement were also found among patients in the LG and HMCLG; improvements among patients in the HMG were significantly greater than they were in the LG (P<0.05). Synergistic action were shown among patients in the HMCLG (P<0.05). CONCLUSION Treatment with Chinese herbal medicine formula Jieduhuayu granules and lactulose may improve cognitive and neurophysiological functions in patients with cirrhosis who have MHE. Compared with lactulose alone, Chinese herbal medicine formula Jieduhuayu granules has higher efficacy of improving cognitive and neurophysiological functions in patients with cirrhosis who have MHE, and the two of them together show synergistic action. TRIAL REGISTRATION NUMBER ACTRN12614000193673.
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Affiliation(s)
- Chun Yao
- Department of Hepatology, First Affiliated Hospital, Guangxi University of Chinese Medicine, PR China.
| | - Guochu Huang
- Guangxi University of Chinese Medicine, Nanning, Guangxi, PR China.
| | - Meng Wang
- Guangxi University of Chinese Medicine, Nanning, Guangxi, PR China.
| | - Meng Xia
- Guangxi University of Chinese Medicine, Nanning, Guangxi, PR China.
| | - Fan Yao
- Guangxi University of Chinese Medicine, Nanning, Guangxi, PR China.
| | - Dengfeng Niu
- Guangxi University of Chinese Medicine, Nanning, Guangxi, PR China.
| | - Yuer Zhang
- Guangxi University of Chinese Medicine, Nanning, Guangxi, PR China.
| | - Shan Li
- Guangxi University of Chinese Medicine, Nanning, Guangxi, PR China.
| | - Yu Zhong
- Guangxi University of Chinese Medicine, Nanning, Guangxi, PR China.
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Waghray N, Waghray A, Mullen K. Treatment options for covert hepatic encephalopathy. ACTA ACUST UNITED AC 2014; 12:229-41. [PMID: 24623592 DOI: 10.1007/s11938-014-0014-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OPINION STATEMENT The main issue with treating covert hepatic encephalopathy (HE) is to establish whether it is cost effective to reverse the neuropsychiatric abnormalities that define this mild form of HE. Until fairly recently, covert HE was rarely diagnosed, but advances in computerized psychometric testing have greatly simplified its detection. The many consequences of covert HE are now being identified, and most have been shown to be reversible with standard HE treatment. Perhaps the most enticing possibility will be the potential that standard HE therapies will postpone the onset of overt HE. This will require further evaluation with large placebo-controlled randomized trials.
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Affiliation(s)
- Nisheet Waghray
- Division of Gastroenterology, MetroHealth Medical Center/Case Western Reserve University, Cleveland, USA,
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