RESUMEN
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that develops in patients with severe liver dysfunction and/or portocaval shunting. Despite more than a century of research into the relationship between liver damage and development of encephalopathy, pathogenetic mechanisms of hepatic encephalopathy have not yet been fully elucidated. It is generally recognized, however, that the main trigger of neurologic complications in hepatic encephalopathy is the neurotoxin ammonia/ammonium, concentration of which in the blood increases to toxic levels (hyperammonemia), when detoxification function of the liver is impaired. Freely penetrating into brain cells and affecting NMDA-receptor-mediated signaling, ammonia triggers a pathological cascade leading to the sharp inhibition of aerobic glucose metabolism, oxidative stress, brain hypoperfusion, nerve cell damage, and formation of neurological deficits. Brain hypoperfusion, in turn, could be due to the impaired oxygen transport function of erythrocytes, because of the disturbed energy metabolism that occurs in the membranes and inside erythrocytes and controls affinity of hemoglobin for oxygen, which determines the degree of oxygenation of blood and tissues. In our recent study, this causal relationship was confirmed and novel ammonium-induced pro-oxidant effect mediated by excessive activation of NMDA receptors leading to impaired oxygen transport function of erythrocytes was revealed. For a more complete evaluation of "erythrocytic" factors that diminish brain oxygenation and lead to encephalopathy, in this study, activity of the enzymes and concentration of metabolites of glycolysis and Rapoport-Lubering shunt, as well as morphological characteristics of erythrocytes from the rats with acute hyperammoniemia were determined. To elucidate the role of NMDA receptors in the above processes, MK-801, a non-competitive receptor antagonist, was used. Based on the obtained results it can be concluded that it is necessary to consider ammonium-induced morphofunctional disorders of erythrocytes and hemoglobinemia which can occur as a result of alterations in highly integrated networks of metabolic pathways may act as an additional systemic "erythrocytic" pathogenetic factor to prevent the onset and progression of cerebral hypoperfusion in hepatic encephalopathy accompanied by hyperammonemia.
Asunto(s)
Metabolismo Energético , Eritrocitos , Encefalopatía Hepática , Oxígeno , Receptores de N-Metil-D-Aspartato , Encefalopatía Hepática/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Eritrocitos/metabolismo , Animales , Humanos , Oxígeno/metabolismo , Ratas , Hiperamonemia/metabolismoRESUMEN
Background: Hepatic encephalopathy (HE) is a neurological disorder resulting from advanced liver injury. HE has a high mortality rate and poor prognosis. The pathogenesis of HE is still unclear, which has led to the lack of a satisfactory specific treatment method. There is increasing evidence that the intestinal flora affects the communication between the gut and the brain in the pathogenesis of HE. Adjusting the intestinal flora has had a beneficial effect on HE in recent studies, and the Qingchang Ligan formula (QCLG) has been shown in previous studies to regulate intestinal flora and metabolites. In this study, we established a thioacetamide-induced HE mouse model to evaluate the protective effect of QCLG on HE and explore its potential mechanism, which also demonstrated that intestinal flora dysbiosis is involved in the pathogenesis of HE. Methods: Mice were intraperitoneally injected with thioacetamide (TAA, 150 mg/kg) to induce HE. Additionally, they were orally administered Qingchang Ligan Formula (QCLG) at a dose of 6.725 g/kg·d for seven days, while control mice received an equal volume of saline via gavage. Subsequently, samples were subjected to 16S ribosomal ribonucleic acid (rRNA) gene sequencing, high-performance liquid chromatography-mass spectrometry (LC-MS), and RNA-sequencing (RNA-seq) analysis. Result: QCLG improved weight loss, cognitive impairment, neurological function scores, blood ammonia, and brain gene expression of interleukin-6 (TNF-α), Interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) induced by HE. Moreover, QCLG increased the levels of liver function indicators, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum TNF-α, IL-1ß, and IL-6. 16S RNA sequencing revealed increased Oscillibacter, Colidextribacter, and Helicobacter in TAA-induced mouse fecal samples. Also, the abundance of Bifidobacterium decreases TAA-induced mouse fecal samples. In contrast, QCLG treatment significantly restored the gut microbial community. Metabolomics indicated significant differences in some metabolites among the normal control, treatment, and model groups, including 5-methoxytryptophan, Daidzein, Stercobilin, and Plumieride (PLU). Conclusion: QCLG can alleviate neuroinflammation and prevent HE caused by liver injury by regulating intestinal flora in mouse models.
Asunto(s)
Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Encefalopatía Hepática , Metabolómica , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Medicamentos Herbarios Chinos/farmacología , Masculino , Tioacetamida/toxicidad , Disbiosis/microbiología , ARN Ribosómico 16S/genética , Ratones Endogámicos C57BLRESUMEN
BACKGROUND AND OBJECTIVES: Emerging research suggests that hyperammonemia may enhance the probability of hepatic encephalopathy (HE), a condition associated with elevated levels of circulating ammonia in patients with cirrhosis. However, some studies indicate that blood ammonia levels may not consistently correlate with the severity of HE, highlighting the complex pathophysiology of this condition. METHODS: A systematic review and meta-analysis through PubMed, Scopus, Embase, Web of Science, and Virtual Health Library were conducted to address this complexity, analyzing and comparing published data on various laboratory parameters, including circulating ammonia, blood creatinine, albumin, sodium, and inflammation markers in cirrhotic patients, both with and without HE. RESULTS: This comprehensive review, which included 81 studies from five reputable databases until June 2024, revealed a significant increase in circulating ammonia levels in cirrhotic patients with HE, particularly those with overt HE. Notably, significant alterations were observed in the circulating creatinine, albumin, sodium, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα) in HE patients. CONCLUSIONS: These findings suggest an association between ammonia and HE and underscore the importance of considering other blood parameters such as creatinine, albumin, sodium, and pro-inflammatory cytokines when devising new treatment strategies for HE.
Asunto(s)
Amoníaco , Encefalopatía Hepática , Cirrosis Hepática , Encefalopatía Hepática/sangre , Humanos , Amoníaco/sangre , Cirrosis Hepática/sangre , Cirrosis Hepática/complicaciones , Biomarcadores/sangre , Creatinina/sangre , Interleucina-6/sangre , Factor de Necrosis Tumoral alfa/sangre , Sodio/sangre , Hiperamonemia/sangre , Albúmina Sérica/análisisRESUMEN
Objective: To explore whether transjugular intrahepatic portosystemic shunt (TIPS) can improve the prognosis of esophagogastric variceal bleeding (EGVB) combined with sarcopenia in cirrhotic patients. Methods: A retrospective cohort study was performed. A total of 464 cases with cirrhotic EGVB who received standard or TIPS treatment between January 2017 and December 2019 were selected. Regular follow-up was performed for the long-term after treatment. The primary outcome was transplantation-free survival. The secondary endpoints were rebleeding and overt hepatic encephalopathy (OHE). The obtained data were statistically analyzed. The t-test and Wilcoxon rank-sum test were used to compare continuous variables between groups. The χ2 test, or Fisher's exact probability test, was used to compare categorical variables between groups. Results: The age of the included patients was 55.27±13.86 years, and 286 cases were male. There were 203 cases of combined sarcopenia and 261 cases of non-combined sarcopenia. The median follow-up period was 43 months. The two groups had no statistically significant difference in follow-up time. There was no statistically significant difference in transplant-free survival between the TIPS group and the standard treatment group in the overall cohort (HR=1.31, 95%CI: 0.97-1.78, P=0.08). The TIPS patient group with cirrhosis combined with sarcopenia had longer transplant-free survival (median survival: 47.76 vs. 52.45, χ2=4.09; HR=1.55, 95CI: 1.01~2.38, P=0.04). There was no statistically significant difference in transplant-free survival between the two kinds of treatments for patients without sarcopenia (HR=1.22, 95%CI: 0.78~1.88, P=0.39). Rebleeding time was prolonged in TIPS patients with or without sarcopenia combination (patients without combined sarcopenia: median rebleeding time: 39.48 vs. 53.61, χ2=18.68; R=2.47, 95CI: 1.67~3.65, P<0.01; patients with sarcopenia: median rebleeding time: 39.91 vs. 50.68, χ2=12.36; HR=2.20, 95CI: 1.42~3.40, P<0.01). TIPS patients had an increased 1-year OHE incidence rate compared to the standard treatment group (sarcopenia patients: 6.93% vs. 16.67%, χ2=3.87, P=0.049; patients without sarcopenia combination: 2.19% vs. 9.68%, χ2=8.85, P=0.01). There was no statistically significant difference in the long-term OHE incidence rate between the two kinds of treatment groups (P>0.05). Conclusion: TIPS can significantly prolong transplant-free survival compared to standard treatment as a secondary prevention of EGVB concomitant with sarcopenia in patients with cirrhosis. However, its advantage is not prominent for patients with cirrhosis in EGVB without sarcopenia.
Asunto(s)
Várices Esofágicas y Gástricas , Hemorragia Gastrointestinal , Cirrosis Hepática , Derivación Portosistémica Intrahepática Transyugular , Sarcopenia , Humanos , Sarcopenia/complicaciones , Derivación Portosistémica Intrahepática Transyugular/métodos , Persona de Mediana Edad , Masculino , Estudios Retrospectivos , Várices Esofágicas y Gástricas/cirugía , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/complicaciones , Femenino , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/cirugía , Cirrosis Hepática/complicaciones , Pronóstico , Anciano , Encefalopatía Hepática/etiología , Resultado del TratamientoRESUMEN
In neurological diseases, the regulation of autophagy plays a crucial role in their pathology, particularly the relationship between autophagy and hepatic encephalopathy (HE) which merits detailed investigation. Glycosphingolipids are abundant and broadly functional in the nervous system and are closely associated with autophagy. However, the specific link and mechanisms between glycosphingolipids and autophagy in HE remain unclear. This study aims to explore the impact of glycosphingolipid changes on the autophagy in HE and its potential mechanisms. Utilizing lectin microarrays, we observed elevated expression levels of α2-3 sialylated glycosphingolipid in the brain tissue of HBV transgenic mice and ammonia-induced astrocyte models, suggesting that the increase in α2-3 sialylated glycosphingolipid is related to HE. Further research revealed that the increased expression of α2-3 sialylated glycosphingolipid, mediated by ST3GAL2, affects autophagy by regulating the autophagy initiation complex Vps34-Beclin-1. In summary, our research not only comprehensively reveals the changes in brain glycosphingolipid during HBV-related HE but also elucidates the interactions and regulatory mechanisms between α2-3 sialylated glycosphingolipid and autophagy. This study provides a new perspective on understanding the pathogenesis of HE and offers novel theories and targets for future research and treatment strategies.
Asunto(s)
Autofagia , Glicoesfingolípidos , Encefalopatía Hepática , Sialiltransferasas , Animales , Encefalopatía Hepática/metabolismo , Encefalopatía Hepática/patología , Ratones , Glicoesfingolípidos/metabolismo , Sialiltransferasas/metabolismo , Sialiltransferasas/genética , Ratones Transgénicos , Encéfalo/metabolismo , Encéfalo/patología , Humanos , beta-Galactosida alfa-2,3-Sialiltransferasa , Astrocitos/metabolismo , MasculinoRESUMEN
Liver cirrhosis has long been considered a point of no return, with limited hope for recovery. However, recent advancements, particularly the Baveno VII criteria and the utilization of transjugular intrahepatic portosystemic shunt (TIPS), have illuminated the concept of hepatic recompensation. In this editorial we comment on the article by Gao et al published in the recent issue. This editorial provides a comprehensive overview of the evolution of understanding cirrhosis, the criteria for recompensation, and the efficacy of TIPS in achieving recompensation. We discuss key findings from recent studies, including the promising outcomes observed in patients who achieved recompensation post-TIPS insertion. While further research is needed to validate these findings and elucidate the mech-anisms underlying recompensation, the insights presented here offer renewed hope for patients with decompensated cirrhosis and highlight the potential of TIPS as a therapeutic option in their management.
Asunto(s)
Cirrosis Hepática , Derivación Portosistémica Intrahepática Transyugular , Derivación Portosistémica Intrahepática Transyugular/métodos , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Humanos , Cirrosis Hepática/cirugía , Cirrosis Hepática/complicaciones , Resultado del Tratamiento , Hipertensión Portal/cirugía , Hipertensión Portal/etiología , Hipertensión Portal/diagnóstico , Encefalopatía Hepática/etiología , Encefalopatía Hepática/cirugíaRESUMEN
Acute hyperammonaemia is a medical emergency as it can progress to cerebral oedema, seizures, coma and death. Hepatic encephalopathy secondary to cirrhotic disease or portosystemic shunting are relatively well-known causes, but non-cirrhotic aetiologies of acute hyperammonaemia are less well-known, especially in the emergency department. However, an elevated ammonia is not required to make the diagnosis of hepatic encephalopathy. Although measurement of plasma ammonia is recommended for patients with acute, unexplained, altered mental status, as early identification allows early effective management which may prevent irreversible brain damage, there is currently reduced awareness among physicians of the non-cirrhotic aetiologies of acute hyperammonaemia. Furthermore, measurement of ammonia in patients with cirrhosis has been shown to have low sensitivity and specificity, and not to have altered management in the majority of cases; thus, measurement of ammonia is currently not recommended in guidelines for management of hepatic encephalopathy. We sought to describe the pathophysiology of hyperammonaemia and review the non-cirrhotic causes. This was achieved by review of MEDLINE, PubMed and Web of Science databases to include published English literature within the last 20 years. We also present a framework for investigating the acute non-cirrhotic causes of hyperammonaemia to assist both chemical pathologists and clinicians managing these often challenging cases.
Asunto(s)
Amoníaco , Encefalopatía Hepática , Hiperamonemia , Humanos , Hiperamonemia/etiología , Hiperamonemia/diagnóstico , Hiperamonemia/fisiopatología , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/etiología , Encefalopatía Hepática/fisiopatología , Amoníaco/sangreRESUMEN
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that can occur in people with acute or chronic liver disease. Here, we investigated the effects of menthol, a natural monoterpene, on HE induced by thioacetamide (TA) in male Wistar rats. The rats received 200 mg/kg of TA twice a week for four weeks and were administered 10 mg/kg of menthol intraperitoneally daily for the same period. The results showed that menthol treatment reduced oxidative stress and inflammation in the livers and hippocampi of the rats that received TA. It also lowered the levels of ammonium and liver enzymes AST, ALT, ALP, and GGT in the serum of these animals and prevented liver histopathological damage. In addition, the expression and activity of acetylcholinesterase in the hippocampus of HE model rats were decreased by menthol. Likewise, this monoterpene reduced the expression of TLR4, MyD88, and NF-κB in the hippocampus while increasing the expression of BDNF and α7-nACh receptor. Menthol also reduced neuronal death in the hippocampal cornu ammonis-1 and dentate gyrus regions and reduced astrocyte swelling, which led to improved learning and spatial memory in rats with HE. In conclusion, the study suggests that menthol may have strong protective effects on the liver and brain, making it a potential treatment for HE and neurodegenerative diseases.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Encefalopatía Hepática , Hipocampo , Mentol , Estrés Oxidativo , Ratas Wistar , Memoria Espacial , Tioacetamida , Receptor Toll-Like 4 , Animales , Masculino , Estrés Oxidativo/efectos de los fármacos , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/metabolismo , Encefalopatía Hepática/inducido químicamente , Encefalopatía Hepática/prevención & control , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ratas , Mentol/farmacología , Memoria Espacial/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Receptor Toll-Like 4/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , FN-kappa B/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Acetilcolinesterasa/metabolismoRESUMEN
BACKGROUND & AIMS: The benefits of prophylactic antibiotics in patients with alcohol-associated hepatitis (AH) receiving steroids remain unclear. We aimed to assess the clinical impact of prophylactic antibiotics in AH patients receiving steroids. METHODS: We systematically reviewed four electronic databases from inception to 30 November 2023. Pooled estimates were analysed using random-effects models. The primary outcome was 90-day survival. Secondary outcomes included infection at days 30 and 90 days, hepatorenal syndrome (HRS), acute kidney injury (AKI), hepatic encephalopathy (HE) and drug-related adverse events (AE). Trial sequential analyses were performed for the primary outcome of 90-day mortality. RESULTS: We screened 419 articles and included six eligible studies (four RCTs and two matched cohort studies) with a total of 510 patients. Compared to standard medical treatment (SMT), prophylactic antibiotics were associated with a lower risk of infection at 30 days (OR: 0.35, 95%CI: 0.20-0.59, I 2 = 0%), infection at 90 days (OR: 0.26, 95%CI: 0.10-0.67, I 2 = 0%) and a lower rate of HE (OR: 0.32, 95%CI: 0.12-0.87, I 2 = 0%). However, prophylactic antibiotics did not improve 90-day survival, sepsis-related mortality, HRS, or AKI. The risks of drug-related AE and fungal infections were similar in patients with AH who received prophylactic antibiotics or SMT. Using trial sequential analysis, the minimum sample size required to detect a 15% relative risk reduction in 90 days mortality with prophylactic antibiotics was 1171. CONCLUSIONS: In hospitalized AH patients receiving steroid therapy, prophylactic antibiotics reduced the risk of infection and HE, but did not improve survival or prevent AKI compared to SMT.
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Antibacterianos , Profilaxis Antibiótica , Hepatitis Alcohólica , Humanos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/prevención & control , Antibacterianos/administración & dosificación , Profilaxis Antibiótica/estadística & datos numéricos , Encefalopatía Hepática/epidemiología , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Hepatitis Alcohólica/complicaciones , Hepatitis Alcohólica/tratamiento farmacológico , Hepatitis Alcohólica/mortalidad , Esteroides/administración & dosificación , Esteroides/efectos adversosRESUMEN
One of the major roles of nanotechnology in the pharmaceutical field is to provide a facility to improve drug delivery systems and design smart nanocarriers with the potential to deliver specific biomolecules to the target site for treatment. This study evaluated Sonchus maritimus-loaded niosomes (SmE-N) in hepatic encephalopathy induced by a high-fructose diet (HFD) in rats. High-performance liquid chromatography (HPLC) analysis of Sonchus maritimus extracts (SmE), the synthesis of niosomes, and their characterization were performed. For the in vivo study, 24 male rats were haphazardly divided into 4 groups (n=6) control, HFD (35%), HFD+SmE-N (50 mg/kg/day), and HFD+metformin (50 mg/kg/day). Clinical behaviors and biological markers were assessed for all groups. The in vitro results of the chromatographic analysis revealed that Sonchus maritimus contains important phenolic acids, including gallic acid, vanillic acid, chlorogenic acid, and caffeic acid, as well as diverse flavonoids, including quercetin, rutin, and naringin bioactive compounds. The niosome formulation, characterized by the encapsulation efficiency of SmE, reached up to 61.40%. The in vivo results of the HFD showed a significant change in behavior parameters, liver glycogen, transaminase enzymes, brain protein, and acetylcholine esterase levels. In addition, there was a significant increase in malondialdehyde levels and a decrease in glutathione, superoxide dismutase, and glutathione peroxidase activities in the HFD group compared to the control group. Furthermore, the histopathological observation recorded a profound modiï¬cation in the liver and brain tissues of the HFD group. In contrast, the treatment with SmE-N and metformin assured a partial amelioration in the noticed parameters compared to the HFD group, but SmE-N led to a better improvement than metformin compared to the control group. In conclusion, the use of SmE-N bioconjugated by linoleic acid seems powerful in treating the complications of fructose-induced metabolic disorders due to its hepato-neuroprotective abilities.
Asunto(s)
Fructosa , Encefalopatía Hepática , Ácido Linoleico , Liposomas , Ratas Wistar , Sonchus , Animales , Masculino , Ratas , Fructosa/administración & dosificación , Sonchus/química , Encefalopatía Hepática/inducido químicamente , Ácido Linoleico/administración & dosificación , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/químicaRESUMEN
BACKGROUND: Gut microbiota (GM) affects the progression and response to treatment in liver diseases. The GM composition is diverse and associated with different etiologies of liver diseases. Notably, alterations in GM alterations are observed in patients with portal hypertension (PH) secondary to cirrhosis, with hepatitis B virus (HBV) infection being a major cause of cirrhosis in China. Thus, understanding the role of GM alterations in patients with HBV infection-related PH is essential. AIM: To evaluate GM alterations in patients with HBV-related PH after transjugular intrahepatic portosystemic shunt (TIPS) placement. METHODS: This was a prospective, observational clinical study. There were 30 patients (with a 100% technical success rate) recruited in the present study. Patients with esophagogastric variceal bleeding due to HBV infection-associated PH who underwent TIPS were enrolled. Stool samples were obtained before and one month after TIPS treatment, and GM was analyzed using 16S ribosomal RNA amplicon sequencing. RESULTS: One month after TIPS placement, 8 patients developed hepatic encephalopathy (HE) and were assigned to the HE group; the other 22 patients were assigned to the non-HE group. There was no substantial disparity in the abundance of GM at the phylum level between the two groups, regardless of TIPS treatment (all, P > 0.05). However, following TIPS placement, the following results were observed: (1) The abundance of Haemophilus and Eggerthella increased, whereas that of Anaerostipes, Dialister, Butyricicoccus, and Oscillospira declined in the HE group; (2) The richness of Eggerthella, Streptococcus, and Bilophila increased, whereas that of Roseburia and Ruminococcus decreased in the non-HE group; and (3) Members from the pathogenic genus Morganella appeared in the HE group but not in the non-HE group. CONCLUSION: Intestinal microbiota-related synergism may predict the risk of HE following TIPS placement in patients with HBV-related PH. Prophylactic microbiome therapies may be useful for preventing and treating HE after TIPS placement.
Asunto(s)
Microbioma Gastrointestinal , Encefalopatía Hepática , Virus de la Hepatitis B , Hipertensión Portal , Derivación Portosistémica Intrahepática Transyugular , Humanos , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Hipertensión Portal/etiología , Hipertensión Portal/diagnóstico , Hipertensión Portal/microbiología , Estudios Prospectivos , Encefalopatía Hepática/etiología , Adulto , Virus de la Hepatitis B/aislamiento & purificación , Heces/microbiología , Cirrosis Hepática/virología , Cirrosis Hepática/microbiología , Cirrosis Hepática/cirugía , China/epidemiología , Resultado del Tratamiento , Hepatitis B/complicaciones , Hepatitis B/diagnóstico , Hepatitis B/virología , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/diagnóstico , Várices Esofágicas y Gástricas/microbiología , Várices Esofágicas y Gástricas/virología , Hemorragia Gastrointestinal/etiología , ARN Ribosómico 16S/genética , Disbiosis/etiología , Anciano , Bacterias/aislamiento & purificación , Bacterias/genéticaRESUMEN
Patients with cirrhosis who have cognitive complaints are presumed to have hepatic encephalopathy (HE), which leads to unwarranted medications while ignoring the underlying disease process causing these complaints. Since neuropsychological testing, the current gold standard for HE diagnosis, is not readily available, an orderable test is needed. We aimed to develop and validate a rapid gut microbiota test to exclude HE and determine stakeholder input on this approach. Stool was collected from two cohorts: a two-center training cohort (n = 305, on/not on HE-related therapy) and a multicenter validation cohort (n = 30, on HE treatment). Stool microbiota was analyzed rapidly using nanopore analysis. Stakeholder (patients and clinicians) needs assessment was evaluated using semi-quantitative questionnaires. In the training cohort, machine learning using neural network identified a 20-species signature that differentiated HE vs no-HE with 84% specificity compared to the gold standard neuropsychological testing. This high specificity persisted regardless of whether patients were on HE-related therapy or not. In the validation cohort, application of this profile led to reevaluation of the HE diagnosis and treatment in > 40% of the patients. This approach was acceptable to patients (Veterans in the validation cohort) and clinician (n = 40 nationwide) stakeholders. We conclude that a machine learning stool signature based on 20 microbial species developed in a training set and validated in a separate multicenter prospective cohort differentiated those with vs. without HE, identified patients misdiagnosed with HE, and was acceptable to patients and clinician stakeholders.
Asunto(s)
Heces , Microbioma Gastrointestinal , Encefalopatía Hepática , Cirrosis Hepática , Humanos , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/microbiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/microbiología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Heces/microbiología , Bacterias/aislamiento & purificación , Bacterias/clasificación , Bacterias/genética , Estudios de Cohortes , Aprendizaje AutomáticoRESUMEN
BACKGROUND: There is growing evidence for a relationship between gut microbiota and hepatic encephalopathy (HE). However, the causal nature of the relationship between gut microbiota and HE has not been thoroughly investigated. METHOD: This study utilized the large-scale genome-wide association studies (GWAS) summary statistics to evaluate the causal association between gut microbiota and HE risk. Specifically, two-sample Mendelian randomization (MR) approach was used to identify the causal microbial taxa for HE. The inverse variance weighted (IVW) method was used as the primary MR analysis. Sensitive analyses were performed to validate the robustness of the results. RESULTS: The IVW method revealed that the genus Bifidobacterium (OR = 0.363, 95% CI: 0.139-0.943, P = 0.037), the family Bifidobacteriaceae (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039), and the order Bifidobacteriales (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039) were negatively associated with HE. However, no causal relationship was observed among them after the Bonferroni correction test. Neither heterogeneity nor horizontal pleiotropy was found in the sensitivity analysis. CONCLUSION: Our MR study demonstrated a potential causal association between Bifidobacterium, Bifidobacteriaceae, and Bifidobacteriales and HE. This finding may provide new therapeutic targets for patients at risk of HE in the future.
Asunto(s)
Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Encefalopatía Hepática , Análisis de la Aleatorización Mendeliana , Humanos , Encefalopatía Hepática/genética , Encefalopatía Hepática/microbiología , Bifidobacterium/genéticaRESUMEN
Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency with symptoms ranging from slight cognitive changes detectable only by neuropsychiatric testing to coma. Up to 60% of patients with cirrhosis have mild forms of HE and 35% will at some point experience overt HE. Even in its milder forms, HE impacts the patient's daily routines, self-sufficiency, quality of life, and, thereby, socio-economic status. HE is a condition affecting the whole household including formal and informal caregivers, who carry a heavy burden. Early identification, prophylaxis, and treatment of HE are essential for relieving patients and informal caregivers.
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Cuidadores , Encefalopatía Hepática , Calidad de Vida , Encefalopatía Hepática/psicología , Humanos , Calidad de Vida/psicología , Cuidadores/psicología , Costo de EnfermedadRESUMEN
Minimal hepatic encephalopathy (MHE) is common in liver cirrhosis and is identified by psychometric tests. The portosystemic hepatic encephalopathy score (PHES) is the most widely used and serves as an inter-study comparator. PHES has not been standardised for use in the Danish population, where German normal values have been applied until now based on the notion that the populations are comparable. This study aimed to evaluate if German PHES normal values can be applied in the Danish population and establish Danish normal values if needed. 200 Danish and 217 German healthy persons underwent Number Connection Test A and B (NCT), Line Tracing Test (LTT), Digit Symbol Test (DST), and Serial Dotting Test (SDT), and based on performance, PHES was calculated. German and Danish PHES performance declined with age in all subtests but more rapidly in Danes. Both German and Danish norms were impacted by gender and education, but to a different extent in the single tests of the test battery. Accordingly, there was a need for specific Danish normal values, which are presented here. Applying the new Danish normal values instead of the German in patients with cirrhosis yielded a lower percentage of out-of-norm performances (58% vs. 66%) and, hence, a lower prevalence of MHE. Danes and Germans perform differently on PHES, and therefore, normal German values cannot be used in Danish patients. Danish normal values are presented here and yield a lower number of 'out of norm' performances.
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Encefalopatía Hepática , Humanos , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/psicología , Encefalopatía Hepática/epidemiología , Masculino , Dinamarca/epidemiología , Femenino , Alemania/epidemiología , Persona de Mediana Edad , Adulto , Anciano , Pruebas Neuropsicológicas , Adulto Joven , Valores de Referencia , Cirrosis Hepática/diagnóstico , Psicometría , Comparación TransculturalRESUMEN
INTRODUCTION: Hepatic encephalopathy (HE) is a frequent complication of cirrhosis, leading to preventable hospitalizations and increased mortality. Despite the availability of validated neuro-psychometric tests to diagnose HE, only 10% of clinicians regularly screen for HE due to lack of time, equipment, and trained personnel. MATERIALS AND METHODS: We studied the association between patient-reported cognitive function and the National Institutes of Health Toolbox Cognition Battery (a validated measure of HE) in patients with cirrhosis. A single-center prospective study of adult patients undergoing liver transplantation evaluation was performed from 10/2020 to 12/2021. Cognition was assessed using the National Institutes of Health Toolbox Cognition Battery and a brief Patient-Reported Outcomes Measurement Information System (PROMIS) survey. RESULTS: Twenty-three liver transplantation candidates were enrolled; the mean age was 56.4 (±9.7) years, 39% were female and the most common etiologies of cirrhosis were primary biliary cirrhosis/primary sclerosing cholangitis/overlap syndrome (30%), hepatitis C (22%) and alcohol-associated liver disease (22%). The mean MELD-Na was 14.9 (±6.4). The mean PROMIS Cognitive Function T-score (PROMISCF) was 49.2 (±9.6). The mean T-scores for the List Sort Working Memory test, Flanker Inhibitory Control and Attention test, and Pattern Comparison Processing Speed test were 46.4 (±9.9), 37.8 (±6.2), and 50.22 (±16.4), respectively. PROMISCF correlated with the List Sort Working Memory test (r = 0.45, P = .03). The mean hospitalization rate was 1.6 days admitted per month. On adjusted multivariate analysis, PROMISCF predicted total hospitalization days (P < .001), hospital admissions (P = .01), and hospitalization rate (P < .001). CONCLUSIONS: A brief survey can screen for HE and predict hospitalizations in patients with cirrhosis.
Asunto(s)
Disfunción Cognitiva , Encefalopatía Hepática , Cirrosis Hepática , Medición de Resultados Informados por el Paciente , Humanos , Masculino , Femenino , Persona de Mediana Edad , Cirrosis Hepática/complicaciones , Cirrosis Hepática/cirugía , Estudios Prospectivos , Disfunción Cognitiva/etiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Encefalopatía Hepática/etiología , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/epidemiología , Trasplante de Hígado , Anciano , Hospitalización , Pruebas Neuropsicológicas , CogniciónRESUMEN
Dengue fever is an important arboviral disease that significantly impacts the disease burden among populations residing in tropical regions. Dengue infection is known to have a broad spectrum of clinical manifestations, which range from fatal, life-threatening shock, encephalitis, and myocarditis to asymptomatic illness. Mild hepatic dysfunction with deranged hepatic laboratory parameters is a known entity with dengue fever. However, dengue presenting as acute liver failure associated with hepatic encephalopathy without shock or signs of plasma leakage is rare. Therefore, we are reporting the case of a young male with dengue fever presented as acute liver failure from a tertiary care center in central India to spread awareness among healthcare professionals worldwide regarding unusual presentations of dengue fever and consideration of dengue fever as a differential diagnosis in patients presenting with acute liver failure, especially in endemic regions.
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Dengue , Encefalopatía Hepática , Fallo Hepático Agudo , Humanos , Encefalopatía Hepática/etiología , Encefalopatía Hepática/virología , Masculino , Dengue/complicaciones , Dengue/diagnóstico , Fallo Hepático Agudo/virología , Fallo Hepático Agudo/etiología , Fallo Hepático Agudo/diagnóstico , Adulto , India , Diagnóstico DiferencialRESUMEN
BACKGROUND/AIMS: Although it is well admitted that cirrhotic patients display various causes of neurocognitive impairment (NI) hampering the diagnosis of covert hepatic encephalopathy (CHE), those are almost never investigated per se. The aims of this study were, in cirrhotic patients displaying cognitive complaints explored by a complete multimodal work-up, to assess: (1) the prevalence of CHE and/or that of other causes of NI and (2) their outcomes, according to the cause of NI. METHODS: Prospective cohort of cirrhotic patients referred in a dedicated clinic because of cognitive complaints. Work-up included a complete neuropsychological assessment, electroencephalogram (EEG) and brain magnetic resonance imaging with spectroscopy. The diagnosis of CHE was made by an adjudication committee involving the physicians/neuropsychologist. RESULTS: One hundred and twenty-three patients were included (alcohol/MASLD/virus in 63/53/14%, MELD = 11). Sixty-six per cent of them were diagnosed with CHE; among them, 73% exhibited also other causes of NI, mainly cerebrovascular diseases/psychiatric. Among patients without CHE, 48% and 59% displayed pathological Psychometric Hepatic Encephalopathy Score and animal naming test, respectively. Clinical improvement was observed in 77% of the patients re-evaluated after specific management. CHE, but not the other causes of NI, was independently associated with OHE occurrence. CONCLUSION: Other causes of NI than CHE are frequent in patients with cirrhosis, and not ruled-out by the classical tests dedicated to CHE. Prognosis was influenced by the cause of NI. The management of patients even without CHE led to clinical improvement, underlining the need for a multifaceted approach of cirrhotic patients with cognitive complaints.
Asunto(s)
Disfunción Cognitiva , Encefalopatía Hepática , Cirrosis Hepática , Pruebas Neuropsicológicas , Humanos , Encefalopatía Hepática/psicología , Masculino , Femenino , Cirrosis Hepática/complicaciones , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Disfunción Cognitiva/etiología , Electroencefalografía , Imagen por Resonancia Magnética , Adulto , PrevalenciaRESUMEN
INTRODUCTION: Acute kidney injury (AKI) is a commonly seen condition in the natural course of cirrhosis. The aim of this study was to evaluate the pooled incidence and risk factors of AKI in different clinical stages and situations in patients with cirrhosis. METHODS: Search was conducted on 13 December 2023 across MEDLINE (PubMed), Embase, and Cochrane databases. Meta-analysis was performed using a generalized linear mixed model. RESULTS: In total, 73 studies with 5,202,232 patients were finally enrolled in the meta-analysis. AKI commonly occurs among hospitalized cirrhotics experiencing any decompensation event (29%) as well as among stable outpatients (28%) throughout a 1-year follow-up period. On admission, patients with infection or sepsis/septic shock had the highest AKI rate (47%), followed by those with hepatic encephalopathy (41%). Furthermore, the severity of liver disease proved to be a substantial driver for AKI development, while patients at intensive care unit had the greatest AKI incidence (61%). CONCLUSIONS: Both hospitalized patients and stable outpatients with cirrhosis exhibited an elevated susceptibility to AKI. Patients at intensive care unit and those with severe liver disease, infection, sepsis/septic shock, hepatic encephalopathy, or acute on chronic liver failure upon admission are at higher risk for AKI. TRIAL REGISTRATION: PROSPERO, registered 09/12/23, CRD42023487736.