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OBJECTIVE: Acute-on-chronic liver failure (ACLF) is a syndrome characterized by a high short-term mortality rate, and effective interventions are still lacking. This study aims to investigate whether the small molecule baicalein can mitigate ACLF and elucidate the molecular mechanisms. METHODS: The ACLF mouse model was induced through chronic liver injury using carbon tetrachloride, followed by acute inflammation induction with lipopolysaccharide (LPS). Baicalein was administered through intraperitoneal injection to explore its therapeutic effects. In vitro experiments utilized the iBMDM macrophage cell line to investigate the underlying mechanisms. Peripheral blood was collected from clinical ACLF patients for validation. RESULTS: In the LPS-induced ACLF mouse model, baicalein demonstrated a significant reduction in acute inflammation and liver damage, as evidenced by histopathological evaluation, liver function analysis, and inflammatory marker measurements. Transcriptomic analysis, coupled with molecular biology experiments, uncovered that baicalein exerts its effects in ACLF by activating the TrKB-CREB1 signaling axis to upregulate the surface expression of the TREM2 receptor on macrophages. This promotes M2 macrophage polarization and activates efferocytosis, thereby inhibiting inflammation and alleviating liver damage. Furthermore, we observed a substantial negative correlation between postoperative peripheral blood plasma soluble TREM2 (sTREM2) levels and inflammation, as well as adverse outcomes in clinical ACLF patients. CONCLUSION: Baicalein plays a protective role in ACLF by enhancing the surface expression of the TREM2 receptor on macrophages, leading to the suppression of inflammation, mitigation of liver damage, and a reduction in mortality. Additionally, plasma sTREM2 emerges as a critical indicator for predicting adverse outcomes in ACLF patients.
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Insuficiencia Hepática Crónica Agudizada , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Flavanonas , Macrófagos , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Receptores Inmunológicos , Transducción de Señal , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Animales , Flavanonas/farmacología , Flavanonas/uso terapéutico , Humanos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Masculino , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Lipopolisacáridos , Regulación hacia Arriba/efectos de los fármacos , Receptor trkB/metabolismo , Modelos Animales de Enfermedad , Persona de Mediana Edad , Femenino , Línea Celular , Adulto , Proteínas Tirosina Quinasas/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacologíaRESUMEN
Major causes of acute insult in Hepatitis B virus related acute on chronic liver failure in the Asian region are reactivation of Hepatitis B virus and super infection with hepatitis A and E virus (ACLF). Anti viral therapy should be started as soon as possible in the ACLF patients at presentation while waiting for confirmation by HBV DNA level. This randomized controlled trial was carried out at the Department of Hepatology, BSMMU, Bangladesh from September 2019 to august 2020 with Hepatitis B virus related ACLF patient. This trial was conducted among twenty seven HBV acute on chronic liver failure patient to compare Child Turcotte pugh (CTP) score, Model for end stage liver disease (MELD) score, Asia Pacific Association for study of Liver (APASL) ACLF Research consortium (AARC) score, survival of the patients and HBV DNA level at 3 months with antiviral therapy between tenofovir alafenamide (25mg) and entecavir (0.5mg) group. CTP score, MELD score and AARC score were significantly (p<0.05) decline from baseline to all subsequent follow-up at 1st (at 7 days), 2nd (at 14 days), 3rd (at 30 days) and 4th (at 90 days) in each group but non significant (p>0.05) difference occurred between two group. All twenty seven patients had detectable HBV DNA level at pre-treatment and all survived patients became undectable at 4th, 90 days follow-up. Total 10 patients (37.07%) were survived at 90 days follow-up, out of them seven patients (70.0%) were in tenofovir alafenamide group and three patients (30.0%) were in entecavir group which was statistically significant (p<0.05) in between two group. Hepatic encephalopathy and hepatorenal syndrome were most common causes of death in both groups. Both drugs tenofovir alafenamide and entecavir significantly improves liver functions but the former one is superior regarding survival.
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Insuficiencia Hepática Crónica Agudizada , Antivirales , Guanina , Tenofovir , Humanos , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Guanina/análogos & derivados , Guanina/uso terapéutico , Antivirales/uso terapéutico , Masculino , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/virología , Insuficiencia Hepática Crónica Agudizada/etiología , Femenino , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Alanina/análogos & derivados , Alanina/uso terapéutico , Hepatitis B/tratamiento farmacológico , Hepatitis B/complicaciones , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/efectos de los fármacosRESUMEN
Objective: To observe the therapeutic effect of Shengsan Jiedu Huayu decoction in alleviating inflammatory liver injury in rats with acute-on-chronic liver failure (ACLF) and its effect on the activation intensity for the NLRP3 signaling pathway. Methods: 63 SD rats were randomly divided into a blank group, a model group, and low-, medium-, and high-dose groups of Shengsan Jiedu Huayu decoction (7.29 g/kg/d, 14.58 g/kg/d, and 29.16 g/kg/d). The ACLF rat model was replicated using carbon tetrachloride combined with d-galactosamine and lipopolysaccharide. Different dose gradients of the Shengsan Jiedu Huayu decoction were used for a five-day intervention treatment, and then rat serum and tissue samples were collected. A biochemical analyzer was used to detect the serum levels of ALT, AST, and TBIL in rats. ELISA was used to detect serum IL-18 and IL-1ß content. HE staining was used to observe histomorphological changes in liver tissue. Immunohistochemistry was used to detect GSDMD expression in liver tissue. Western blot and PCR were used to detect NLRP3, Caspase1, ASC, TLR4, IL-1ß, IL-18 protein, and mRNA expression levels.The groups were compared using analysis of variance and the rank-sum test. Results: Compared with the blank group, the model group's rat liver tissue was severely injured. Serum levels of ALT, AST, and TBIL, inflammatory factors IL-1ß and IL-18, and the GSDMD protein expression level, NLRP3 expression level, TLR4, caspase 1, ASC, IL-1ß, IL-18 protein, and mRNA (P<0.01) were all significantly increased in the model than the blank group (P<0.01). Additionally, compared with the model group, the low-, medium-, and high-dose groups of Shengsan Jiedu Huayu decoction had improved liver tissue injury in ACLF rats, while the serum levels of ALT, AST, TBIL, IL-1ß, IL-18, liver tissue GSDMD protein, NLRP3, TLR4, caspase 1, and ASC expressions were all lower in the different dose gradients of the Shengsan Jiedu Huayu decoction than the model group, with the most evident reduction in the high-dose group (P<0.01). Conclusion: Shengsan Jiedu Huayu decoction can weaken the activation intensity of the NLRP3 signaling pathway, alleviate liver tissue pathological injury, reduce inflammatory factor release, and alleviate inflammatory liver injury in ACLF rats.
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Insuficiencia Hepática Crónica Agudizada , Medicamentos Herbarios Chinos , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Animales , Ratas , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/etiología , Proteínas Portadoras/metabolismo , Medicamentos Herbarios Chinos/farmacología , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Proteína con Dominio Pirina 3 de la Familia NLR/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Inflamación/tratamiento farmacológicoRESUMEN
BACKGROUND AND AIMS: Terlipressin infusion is effective in hepatorenal syndrome (HRS-AKI). However, its efficacy for HRS-AKI resolution in acute-on-chronic liver failure (ACLF) patients has been suboptimal. Progression of AKI is rapid in ACLF. We investigated whether early initiation of terlipressin(eTerli) can improve response rates. METHODS: Consecutive ACLF patients with stage II/III AKI despite albumin resuscitation (40 g) were randomized to receive terlipressin at 2 mg/24 h plus albumin at 12 h (ET, n = 35) or at 48 h as standard therapy (ST, n = 35). (June 22, 2020 to June 10, 2022). The primary end-point was AKI reversal by day7. RESULTS: Baseline parameters including AKI stage and ACLF-AARC scores in two arms were comparable. Full AKI response at day 7 was higher in ET [24/35 (68.6%)] than ST arm [11/35 (31.4%; P 0.03]. Day3 AKI response was also higher in ET arm [11/35 (31.4%) vs. 4/35 (11.4%), P 0.04]. Using ST compared to ET [HR 4.3; P 0.026] and day 3 serum creatinine > 1.6 mg/dl [HR 9.1; AUROC-0.866; P < 0.001] predicted HRS-AKI non-response at day 7. ET patients showed greater improvement in ACLF grade, mean arterial pressure, and urine output at day 3, and required lower albumin within 7 days than ET arm (149.1 ± 41.8 g vs. 177.5 ± 40.3 g, P 0.006) and had lower 28-day mortality: 40% vs. 65.7%, P 0.031]. Early use of terlipressin than ST [HR 2.079; P 0.038], baseline HE [HR 2.929; P 0.018], and AKI persistence at day 3 [HR 1.369; P 0.011] predicted 28-day mortality. Fifteen (21.4%) patients had treatment related adverse effects, none was life threatening. CONCLUSION: In ACLF patients, early initiation of terlipressin for AKI persisting after 12 h of volume expansion with albumin helps in reduced short-term mortality and early AKI reversal with regression of ACLF stage. These results indicate need for change in current practice for terlipressin usage in HRS-AKI.
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Lesión Renal Aguda , Insuficiencia Hepática Crónica Agudizada , Terlipresina , Vasoconstrictores , Humanos , Terlipresina/administración & dosificación , Masculino , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/diagnóstico , Femenino , Persona de Mediana Edad , Vasoconstrictores/administración & dosificación , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/complicaciones , Insuficiencia Hepática Crónica Agudizada/mortalidad , Adulto , Resultado del Tratamiento , Anciano , Factores de Tiempo , Tiempo de TratamientoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional herbal pair Paeoniae Radix Rubra (roots of Paeonia lactiflora Pall., Chishao in Chinese) and Aconiti Lateralis Radix Praeparata (lateral roots of Aconitum carmichaelii Debeaux, Fuzi in Chinese) are widely used for the treatment of liver diseases, demonstrating clinical efficacy against acute-on-chronic liver failure (ACLF). As the core drug pair representing the "clearing method" and "warming method" in traditional Chinese medicine (TCM), they align with the TCM syndromic characteristics of ACLF, characterized by a mixture of deficiencies and realities. However, the molecular mechanisms underlying the anti-ACLF effects of Chishao - Fuzi herbal pair remain unclear. AIM OF THE STUDY: To reveal the immunoinflammatory status of patients with hepatitis B virus-related ACLF (HBV-ACLF) based on macrophage polarization and to explore the mechanism of action of Chishao - Fuzi herbal pair in regulating macrophage polarization against ACLF. MATERIALS AND METHODS: Peripheral blood samples were prospectively obtained from patients with HBV-ACLF, patients with chronic hepatitis B (CHB) in the immunoactive phase and healthy individuals. Flow cytometry, qRT-qPCR, and ELISA were used to reveal the activation status of monocyte-macrophages and the expression differences in related cytokines in the peripheral blood of patients with HBV-ACLF. Then, an ACLF rat model and a macrophage inflammation model in vitro were established. Hematoxylin-eosin staining, immunohistochemical staining, transmission electron microscopy, flow cytometry, western blotting, RT-qPCR, and ELISA were used to observe changes in the expression of M1/M2 macrophage markers and related inflammatory factors after Chishao - Fuzi herbal pair intervention, both in vivo and in vitro. RESULTS: Patients with HBV-ACLF exhibited an imbalance in M1/M2 macrophage polarization, showing a tendency to activate M1 macrophages with high expression of CD86 and iNOS. This imbalance led to an increase in relevant pro-inflammatory factors (IL-1ß, IL-6, TNF-α) and a decrease in anti-inflammatory factors (IL-10, TGF-ß, VEGF), exacerbating the uncontrolled immune-inflammatory response. Chishao - Fuzi herbal pair intervention improved liver function, coagulation function, and histopathological injury in ACLF rats. It also partially ameliorated endotoxemia and inflammatory injury in ACLF. The mechanism was to restore the immune-inflammatory imbalance and prevent the exacerbation of inflammatory response to liver failure by promoting macrophage polarization toward M2 anti-inflammatory direction, inhibiting M1 macrophage activation, and increasing the levels of anti-inflammatory factors and decreasing pro-inflammatory factors. CONCLUSION: Chishao - Fuzi herbal pair can reduce the systemic inflammatory burden of liver failure by modulating macrophage polarization and restoring ACLF immune-inflammatory imbalance. This study provides new perspectives and strategies for studying HBV-ACLF immune reconstitution and inflammatory response control.
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Insuficiencia Hepática Crónica Agudizada , Diterpenos , Medicamentos Herbarios Chinos , Humanos , Ratas , Animales , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Macrófagos , Antiinflamatorios/farmacologíaRESUMEN
BACKGROUND: Acute-on-chronic liver failure (ACLF) is a common clinical type of liver failure, and patients with acute-on-chronic liver failure are prone to fungal infections, especially the increasing incidence of invasive pulmonary aspergillosis (IPA). Voriconazole is recommended as the first-line antifungal agent in the treatment of invasive aspergillosis; however, no recommendation has been given for patients with severe liver cirrhosis (Child-Pugh C) and liver failure. This trial aims to examine the therapeutic effects and safety of voriconazole in the treatment of IPA in patients with liver failure. METHODS: This study is a non-double-blind randomized controlled trial. The 96 eligible acute-on-chronic liver failure patients complicated with invasive pulmonary aspergillosis will be randomly assigned to receive either the optimized voriconazole regimen or the recommended voriconazole regimen for patients with mild to moderate liver cirrhosis (Child-Pugh A and B), at a 1:1 ratio, with an 8-week follow-up period. The antifungal efficacy of voriconazole will be the primary outcome measure. Plasma voriconazole trough concentration, the laboratory examination (CRP, PCT, ESR, etc.), chest CT, adverse events, and mortality at week 4 and 8 will be the secondary outcome measures. DISCUSSION: This trial aims to demonstrate the efficacy and safety of voriconazole in the treatment of IPA in patients with liver failure, which is expected to provide a reference for scientific optimization of voriconazole regimens and a realistic basis for the standardized treatment of acute-on-chronic liver failure patients complicated with invasive pulmonary aspergillosis. TRIAL REGISTRATION: The trial was registered with the Chinese Clinical Trial Registry, ChiCTR2100048259. Registered on 5 July 2021.
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Insuficiencia Hepática Crónica Agudizada , Aspergilosis Pulmonar Invasiva , Humanos , Voriconazol/efectos adversos , Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/complicaciones , Insuficiencia Hepática Crónica Agudizada/inducido químicamente , Insuficiencia Hepática Crónica Agudizada/complicaciones , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Resultado del Tratamiento , Antifúngicos/efectos adversos , Cirrosis Hepática/complicaciones , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Oral nucleoside (acid) analogues (NAs) are recommended for patients with acute-on-chronic liver failure (ACLF) associated with hepatitis B virus (HBV-ACLF). The efficacy and safety of tenofovir (TDF) and entecavir (ETV) in these patients remain unclear. METHODS: A comprehensive literature search in PubMed, Web of Science, The Cochrane Library, and Embase database was conducted to select studies published before December 2022 on TDF or ETV for HBV-ACLF. The primary outcomes were survival rates at 4, 12, and 48 weeks. Secondary outcomes were virologic and biochemical responses, serum antigen conversion, liver function score, and safety. RESULTS: Four prospective and one retrospective cohort studies were selected. The overall analysis showed comparable survival rates at 4, 12, and 48 weeks for all patients receiving TDF or ETV (4-week: RR = 1.17, 95% CI: 0.90-1.51, p = 0.24; 12-week: RR = 1.00, 95% CI: 0.88-1.13, p = 0.94; 48-week: RR = 0.96, 95% CI: 0.58-1.57, p = 0.86). Child-Turcotte-Pugh (CTP) score and model for end-stage liver disease (MELD) score at 12 weeks were comparable in both groups but lower than baseline (CTP: SMD = -0.75, 95% CI:-2.81-1.30, p = 0.47; MELD: SMD = -1.10, 95% CI:-2.29-0.08, p = 0.07). At 48 weeks, estimated glomerular filtration rate (eGFR) levels were found to decrease to different degrees from baseline in both the TDF and ETV groups, and the decrease was greater in the TDF group than in the ETV group. No significant differences were found in biochemical, virologic response, and serum antigen conversion between the two groups during the observation period. CONCLUSION: TDF treatment of HBV-ACLF is similar to ETV in improving survival, liver function, and virologic response but the effects on renal function in two groups in the long term remain unclear. More and larger long-term clinical trials are required to confirm these findings.
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Insuficiencia Hepática Crónica Agudizada , Enfermedad Hepática en Estado Terminal , Hepatitis B Crónica , Hepatitis B , Humanos , Tenofovir/efectos adversos , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Antivirales/efectos adversos , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Estudios Retrospectivos , Estudios Prospectivos , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Hepatitis B/complicaciones , Hepatitis B/tratamiento farmacológico , Virus de la Hepatitis BRESUMEN
BACKGROUND AND OBJECTIVES: The safety and efficacy of granulocyte-colony stimulating factor (G-CSF) for the treatment of acute-on-chronic liver failure (ACLF) remain controversial. This meta-analysis aimed to evaluate the effectiveness and safety of G-CSF in treating ACLF. METHODS: The estimated pooled risk ratio (RR) and 95% confidence interval (CI) assessed the treatment effects of G-CSF. Mean differences (MD) and 95% confidence intervals were used to analyze continuous data. Heterogeneity was explored by sensitivity analysis. Potential publication bias was assessed using Egger's test. RESULTS: Ten studies, comprising a total of 603 participants, were included in the analysis. The G-CSF group showed significantly lower MELD scores at 7-day (MD = -2.39, 95%CI: -3.95 to -0.82), CTP scores at 7-day (MD = -0.77, 95%CI: -1.41 to -0.14), and MELD scores at 30-day (MD = -3.01, 95%CI: -5.36 to -0.67) compared to the control group. Furthermore, the G-CSF group was associated with a reduced risk of sepsis (RR = 0.53, 95%CI: 0.35-0.80). The 30-day survival (RR = 1.26, 95%CI:1.10-1.43), 60-day survival (RR = 1.47, 95%CI:1.17-1.84, and 90-day survival (RR = 1.73, 95%CI: 1.27-2.35) of patients with ACLF treated with G-CSF were significantly higher than those of the control group. CONCLUSIONS: Our meta-analysis suggests that G-CSF therapy may be a promising treatment for ACLF, with significant improvements in liver function and survival rates, however, further studies are needed to verify this conclusion.
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Insuficiencia Hepática Crónica Agudizada , Factor Estimulante de Colonias de Granulocitos , Humanos , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , SepsisRESUMEN
OBJECTIVE: Acute-on-chronic liver failure (ACLF) causes organ system failures in patients and increases the risk of mortality. One of the main predictors of ACLF development in patients is the severity of systemic inflammation. The purpose of this study was to explore the effects of resolvin D1 (RvD1) on the rat model of ACLF. METHODS: The ACLF rats were induced by first intraperitoneally (ip) injecting CCl4 and porcine serum for 6 weeks to establish the chronic liver injury, followed by once administration (ip) of lipopolysaccharide and d-galactose d-GalN to cause acute liver injury (ALI). An hour before the ALI-induced treatment, rats were administrated (ip) with 0.9% saline or different doses of RvD1 (0.3 or 1 µg/kg). Afterward, the control and treated rats were killed and samples were collected. Biochemical analysis, hematoxylin-eosin and Sirius red staining, flow cytometry assay, and real-time polymerase chain reaction were used to assess the rat liver histopathological injury, the percentage of Treg cells in the spleen, and the messenger RNA (mRNA) levels of transcription factors and immunologic cytokines in liver. RESULTS: The necroinflammatory scores and the serum levels of transaminase significantly increased in ACLF rats compared with those in control rats. These impaired changes observed in ACLF rats could be attenuated by the administration of a low dose of RvD1 before the induction of ALI, which was associated with the increased proportion of regulatory T cells (Treg) in the spleen together with the increased gene expression ratio of Foxp3/RORγt and decreased mRNA level of Il-17a and Il-6 in the liver. CONCLUSION: A low dose of RvD1 can promote the resolution of inflammation in ACLF rats by increasing the proportion of Treg cells. RvD1, therefore, may be used as a potential drug for the treatment of patients with ACLF.
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Insuficiencia Hepática Crónica Agudizada , Linfocitos T Reguladores , Humanos , Ratas , Animales , Porcinos , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , ARN Mensajero/metabolismoRESUMEN
Objective: This study aimed to assess the relationship between glucocorticoid treatment and mortality among patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). Methods: We conducted a retrospective, hospital-based cohort study from 2019 to 2022, including 394 consecutively enrolled HBV-ACLF patients at the Third Affiliated Hospital of Chongqing Medical University. We recorded patient demographics, liver function, CD163 concentration, Model for End-Stage Liver Disease (MELD) score, and complications. The primary endpoint was 30-day mortality. Results: No significant differences were observed between the glucocorticoid-treated and non-glucocorticoid groups regarding sex, age, liver function, complications, or plasma CD163 concentration. After treatment, the median levels of total bilirubin (TBil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), international normalized ratio (INR), and HBV DNA were 322.9 (IQR 258.6-383.3) µmol/L, 354.4 (IQR 253.1-444.6) U/L, 258.4 (IQR 186.4-322.4) U/L, 2.3 (IQR 2.1-2.5), and 5.0 (IQR 4.0-6.0) log IU/mL, respectively. Changes in ALT, AST, sCD163, TBil, INR, and MELD score before and after treatment showed no statistical differences between the glucocorticoid and non-glucocorticoid groups (P > .05). However, the mortality rate was significantly lower in the glucocorticoid group compared to the non-glucocorticoid group (11.2% vs. 29.9%, respectively; P < .001). Multivariable analysis revealed that, after adjusting for confounders, non-glucocorticoid treatment was associated with a higher adjusted hazard ratio (HR) for mortality (HR = 3.7, 95% CI 2.2-6.2) compared to glucocorticoid treatment. Additionally, an interaction test indicated that the association between non-glucocorticoid treatment and mortality was more robust in the sCD163 ≥ 18.2 mg/L group (HR = 7.6, 95% CI 2.9-19.9) but weaker in the sCD163 < 18.2 mg/L group (HR = 2.2, 95% CI 1.2-4.3) (P for interaction < .05). Conclusions: These findings suggest that glucocorticoids are an effective treatment for reducing mortality in HBV-ACLF patients, with particular effectiveness observed in patients with high sCD163 concentrations.
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Insuficiencia Hepática Crónica Agudizada , Enfermedad Hepática en Estado Terminal , Humanos , Virus de la Hepatitis B , Glucocorticoides/uso terapéutico , Estudios de Cohortes , Estudios Retrospectivos , Enfermedad Hepática en Estado Terminal/complicaciones , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/etiología , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Acute-on-chronic liver failure (ACLF) is a fatal complication of cirrhosis. Hence, identification of risk factors for ACLF is crucial. Previous studies have linked proton pump inhibitor (PPI) treatment to complications of cirrhosis, however, a possible effect of PPI treatment on the risk of ACLF has not been investigated yet. Therefore, the present study aimed to characterize the impact of PPI treatment on ACLF development. METHODS: A total of 642 patients hospitalized due to complications of cirrhosis were retrospectively identified, and PPI treatment during an observation period of 3 years following the hospitalization was reviewed. Subsequently, 74 patients with newly initiated PPI treatment at the time of hospitalization (PPI group) were 1:1 propensity score matched to 74 patients who received no PPI treatment (no-PPI group). Primary end point was the development of ACLF during the observation period, and secondary endpoints were mortality and upper gastrointestinal bleeding. RESULTS: PPI and no-PPI groups had comparably severe chronic liver disease at baseline. Nevertheless, the cumulative incidence of ACLF in the presence of death as competing risk was markedly higher in the PPI group compared with the no-PPI group. ACLF-related deaths contributed significantly to a higher 3-year mortality in the PPI group. Uni and multivariable competing risk regression models confirmed that PPI treatment was an independent predictor of ACLF in the study collective (subdistribution HR: 1.892, 95% CI: 1.092-3.281, p = 0.023). The impact of PPI treatment on ACLF development was particularly strong in patients with a model for end-stage liver disease score >12. Upper gastrointestinal bleeding was slightly less frequent in the PPI group. CONCLUSIONS: The present results indicate that PPI treatment could be a risk factor for ACLF in patients with advanced cirrhosis.
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Insuficiencia Hepática Crónica Agudizada , Enfermedad Hepática en Estado Terminal , Humanos , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/epidemiología , Insuficiencia Hepática Crónica Agudizada/etiología , Inhibidores de la Bomba de Protones/efectos adversos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológicoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Yi-Qi-Jian-Pi formula (YQJPF) is a commonly used traditional Chinese medicine (TCM) compound used to treat acute-on-chronic liver failure (ACLF) in China, but its specific mechanism of action has not been fully clarified. AIM OF THE STUDY: The aim of this study was to determine the effect of YQJPF on liver injury and hepatocyte pyroptosis in rats and further explore its molecular mechanism of action. MATERIALS AND METHODS: This study established carbon tetrachloride (CCl4)-, lipopolysaccharide (LPS)- and D-galactose (D-Gal)-induced in vivo models of ACLF in rats and in vitro LPS-induced hepatocyte injury models. Animal experiments were divided into the following groups: control, ACLF model, groups with different doses of YQJPF (5.4, 10.8, and 21.6 g/kg), and western medicine (methylprednisolone). There were 7 rats in the control group and 11 in the other groups. Serological, immunohistochemical, and pathological analyses were used to observe the effect of YQJPF on the liver of ACLF rats. The protective effect of YQJPF on hepatocytes was further verified by RT-qPCR, western blotting, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and other methods. RESULTS: YQJPF significantly improved liver injury in vivo and in vitro, which depended on the regulation of hepatocyte NLRP3/GSDMD-induced pyroptosis. In addition, we found that mitochondrial membrane potential and ATP production decreased after LPS treatment of hepatocytes, which suggested that YQJPF may improve mitochondrial energy metabolism disorders in hepatocytes. We administered a hepatocyte mitochondrial uncoupling agent, FCCP, to determine whether mitochondrial metabolic disorders affected cell pyroptosis. The results showed that the expression of IL-18, IL-1ß, and NLRP3 proteins increased significantly, indicating that the effect of this drug on hepatocyte pyroptosis may be related to mitochondrial metabolism disorders. We found that YQJPF significantly restored the tricarboxylic acid (TCA) cycle rate-limiting enzyme activity and affected the content of TCA metabolites. Furthermore, we revealed that the IDH2 gene, which plays a unique role in ACLF, is a key factor in the regulation of the mitochondrial TCA cycle and can be upregulated under the action of YQJPF. CONCLUSIONS: YQJPF can inhibit classical pyroptosis in hepatocytes by regulating TCA cycle metabolism, thus alleviating liver injury, and IDH2 may be a potential upstream regulatory target of YQJPF.
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Insuficiencia Hepática Crónica Agudizada , Ratas , Animales , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/metabolismo , Insuficiencia Hepática Crónica Agudizada/patología , Piroptosis , Ciclo del Ácido Cítrico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Lipopolisacáridos/farmacología , HepatocitosRESUMEN
Acute-on-chronic liver failure (ACLF) is defined as a syndrome of acutely decompensated cirrhosis in patients with chronic liver disease (CLD). Here we report an ACLF case caused by a flare of occult hepatitis C infection. This patient was infected with hepatitis C virus (HCV) more than a decade ago and hospitalized due to alcohol-associated CLD. Upon admission, the HCV RNA in the serum was negative and the anti-HCV antibody was positive, whereas the viral RNA in the plasma dramatically increased during hospitalization, which suggests an occult hepatitis C infection. Overlapped fragments encompassing the nearly whole HCV viral genome were amplified, cloned, and sequenced. Phylogenetic analysis indicated an HCV genotype 3b strain. Sanger sequencing to 10-fold coverage of the 9.4-kb nearly whole genome reveals high diversity of viral quasispecies, an indicator of chronic infection. Inherent resistance-associated substitutions (RASs) in the NS3 and NS5A but not in the NS5B regions were identified. The patient developed liver failure and accepted liver transplantation, followed by direct-acting antiviral (DAA) treatment. The hepatitis C was cured by the DAA treatment despite the existence of RASs. Thus, care should be taken for occult hepatitis C in patients with alcoholic cirrhosis. The analysis of viral genetic diversity may help to identify an occult hepatitis C virus infection and predict the efficacy of anti-viral treatment.
Asunto(s)
Insuficiencia Hepática Crónica Agudizada , Hepatitis A , Hepatitis C Crónica , Hepatitis C , Humanos , Antivirales/farmacología , Hepacivirus/genética , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Filogenia , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Genotipo , Hepatitis A/tratamiento farmacológico , Genómica , Farmacorresistencia Viral/genética , Proteínas no Estructurales Virales/genética , Insuficiencia del TratamientoRESUMEN
BACKGROUND AND AIMS: Early identification of non-response to steroids is critical in patients with autoimmune hepatitis (AIH) causing acute-on-chronic liver failure (ACLF). We assessed if this non-response can be accurately identified within first few days of treatment. METHODS: Patients with AIH-ACLF without baseline infection/hepatic encephalopathy were identified from APASL ACLF research consortium (AARC) database. Diagnosis of AIH-ACLF was based mainly on histology. Those treated with steroids were assessed for non-response (defined as death or liver transplant at 90 days for present study). Laboratory parameters, AARC, and model for end-stage liver disease (MELD) scores were assessed at baseline and day 3 to identify early non-response. Utility of dynamic SURFASA score [- 6.80 + 1.92*(D0-INR) + 1.94*(∆%3-INR) + 1.64*(∆%3-bilirubin)] was also evaluated. The performance of early predictors was compared with changes in MELD score at 2 weeks. RESULTS: Fifty-five out of one hundred and sixty-five patients (age-38.2 ± 15.0 years, 67.2% females) with AIH-ACLF [median MELD 24 (IQR: 22-27); median AARC score 7 (6-9)] given oral prednisolone 40 (20-40) mg per day were analyzed. The 90 day transplant-free survival in this cohort was 45.7% with worse outcomes in those with incident infections (56% vs 28.0%, p = 0.03). The AUROC of pre-therapy AARC score [0.842 (95% CI 0.754-0.93)], MELD [0.837 (95% CI 0.733-0.94)] score and SURFASA score [0.795 (95% CI 0.678-0.911)] were as accurate as ∆MELD at 2 weeks [0.770 (95% CI 0.687-0.845), p = 0.526] and better than ∆MELD at 3 days [0.541 (95% CI 0.395, 0.687), p < 0.001] to predict non-response. Combination of AARC score > 6, MELD score > 24 with SURFASA score ≥ - 1.2, could identify non-responders at day 3 (concomitant- 75% vs either - 42%, p < 0.001). CONCLUSION: Baseline AARC score, MELD score, and the dynamic SURFASA score on day 3 can accurately identify early non-response to steroids in AIH-ACLF.
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Insuficiencia Hepática Crónica Agudizada , Enfermedad Hepática en Estado Terminal , Hepatitis Autoinmune , Femenino , Humanos , Masculino , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/etiología , Pronóstico , Hepatitis Autoinmune/complicaciones , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/tratamiento farmacológico , Enfermedad Hepática en Estado Terminal/complicaciones , Índice de Severidad de la Enfermedad , Prednisolona/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: We aimed to determine whether the methylation status of thymosin ß4 (Tß4) promoter reflects the severity of acute-on-chronic hepatitis B liver failure (ACHBLF) and whether glucocorticoids affect this status. METHODS: Fifty-six patients with ACHBLF, 45 with chronic hepatitis B (CHB) and 32 healthy controls (HCs), were retrospectively enrolled. Methylation-specific PCR and real-time PCR were used to detect Tß4 methylation frequency and mRNA level. The expression of Tß4 was measured before and after glucocorticoid treatment in patients with ACHBLF. Clinical and laboratory parameters were obtained. RESULTS: Tß4 mRNA expression of patients with ACHBLF was lower than in patients with CHB or HCs, but the methylation frequency was higher. Tß4 promoter methylation frequency was correlated with serum total bilirubin, prothrombin activity and model for end-stage liver disease score. Moreover, Tß4 promoter methylation frequency decreased and demethylation occurred during glucocorticoid therapy. After glucocorticoid therapy, Tß4 mRNA expression and liver function were better in patients with low levels of methylation than in those with higher levels. After 90 d, the survival of patients with low levels of methylation was significantly higher than those with high levels. CONCLUSIONS: Patients with ACHBLF who have low levels of Tß4 methylation may show a more favorable response to glucocorticoid treatment.
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Insuficiencia Hepática Crónica Agudizada , Enfermedad Hepática en Estado Terminal , Hepatitis B Crónica , Humanos , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/genética , Enfermedad Hepática en Estado Terminal/complicaciones , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/genética , ARN MensajeroRESUMEN
BACKGROUND AND AIMS: A dysfunctional immune response is key to the pathogenesis of acute-on-chronic liver failure (ACLF). It has been suggested that treatment with granulocyte colony-stimulating factor (G-CSF) increases survival in patients with ACLF by improving immune cell dysfunction and promoting liver regeneration. The aim of the study is to evaluate the survival benefit associated with G-CSF administration compared with standard medical therapy (SMT) in ACLF. METHODS: Systematic review and meta-analysis of randomized controlled trials. The primary outcome was survival at 60-90 days. We searched Ovid Medline, EMBASE, and Cochrane Central Register of Controlled Trials from inception to August 2021. Manual searches of reference lists in relevant articles and conference proceedings were also included. The revised Cochrane risk-of-bias tool was used for quality and risk of bias assessment. Two independent investigators extracted the data, and disagreements were solved by a third collaborator. RESULTS: The initial search identified 142 studies. Four randomized controlled trials were selected for quantitative analysis including 310 patients (154 G-CSF and 156 SMT). Significant heterogeneity was observed (I2=74%, Chi2=11.57, p=0.009). G-CSF administration did not improve survival in patients with ACLF (random-effects model, risk ratio=0.64 [95% CI 0.39, 1.07]). However, when considering only the results from the studies performed in Asia, a significant decrease on mortality was observed (risk ratio=0.53 [95% CI 0.35, 0.81]). Severity scores (MELD and Child) and CD34+ peripheral cells mobilization did not significantly improve with G-CSF. CONCLUSION: In a systematic review and meta-analysis, G-CSF administration did not significantly improve overall survival compared to SMT in patients with ACLF. The beneficial effects observed in Asian studies, as opposed to the European region, suggest that specific populations may benefit from further research aiming to identify certain subgroups with favourable outcomes when using G-CSF.
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Insuficiencia Hepática Crónica Agudizada , Niño , Humanos , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Granulocitos , AsiaRESUMEN
Objective: To explore the significance of triggering receptor expressed on myeloid cells-2 (TREM-2) prognostic evaluation so as to provide novel biological markers in clinical practice for patients with hepatitis B virus-related acute-on-chronic liver failure ( HBV-ACLF). Methods: The research subjects of this study were divided into an experimental group and a control group. Fifty HBV-ACLF cases admitted to the Department of Infectious Diseases of the First Affiliated Hospital of Nanchang University from January 1, 2019 to December 31, 2019 were selected as the experimental group. Patients were divided into survival and death groups according to the actual prognosis at discharge (self-discharge and dead patients were considered death groups, and all enrolled patients were hospitalized for more than 28 days). Twenty-five healthy subjects were chosen as the control group. Peripheral venous blood was collected from the experimental group and the control group. Plasma and peripheral blood mononuclear cells (PBMC) were isolated. The concentrations of TREM-2, interleukin (IL)-6, and IL-8 were detected in the plasma. TREM-2 mRNA expression was detected in PBMC. A single blood sample was collected from the control group, whereas five blood samples were dynamically collected from the experimental group on the day of admittance and at 7, 14, 21, and 28 days after treatment commenced. Simultaneously, upon admission, the relevant clinical indicators of HBV-ACLF patients were monitored, including the liver function test: alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, coagulation function test: international normalized ratio, prothrombin time, and other indicators. Measurement data were expressed as mean±standard deviation (x±s). Count data were compared and analyzed using the χ(2) test. The intra-group factor mean was compared using a repeated measures ANOVA. The means were analyzed by t-tests between the two groups. Bivariate correlation analysis was used to analyze the correlation between the two variables. The value of TREM-2 as a diagnostic marker was analyzed using the receiver operating characteristic (ROC) curve. Results: The mRNA expression of TREM-2 in the PBMC of HBV-ACLF patients showed a gradually increasing trend at various time points and was significantly higher in the survival group than that of the control group at 28 days (P < 0.01), while the death group showed a gradually weakening trend at various time points and was significantly lower than the control group at 28 days (P < 0.01). (1) The levels of TREM-2 in the plasma of HBV-ACLF patients generally showed a gradually increasing trend at various time points in the survival group. The levels on the day of admission and 7, 14, 21, and 28 days after the initiation of treatment were (1.49±0.85), (1.62±0.58), (1.95±0.69), (2.33±0.71), and (2.00±0.67) ng/ml, respectively. The expression of TREM-2 in the death group showed a gradually weakening trend at various time points. The levels on the day of admission and 7, 14, 21, and 28 days after initiation of treatment were (1.40±0.73), (1.59±0.79), (1.56±0.80), (1.05±0.49), and (0.81±0.21) ng/ml, respectively. The survival group's various detection time points were higher than those of the death group, and the difference was statistically significant. The plasma level of TREM-2 in the healthy control group was (1.25±0.35) ng/ml. (2) The concentrations of IL-6 and IL-8 in the plasma of HBV-ACLF patients showed a gradually decreasing trend at various time points in the survival group. The levels on the day of admission and 7, 14, 21, and 28 days after initiation of treatment were (46.70±26.31), (33.98±20.28), (19.07±10.24), (14.76±7.84), (9.12±7.65) and (108.29±47.07), (93.85±26.53), (79.27±34.63), (56.72 ±18.30), (37.81±13.88) pg/ml, respectively. However, its concentration in the death group fluctuated within a relatively high range. The levels on the day of admission and 7, 14, 21, and 28 days after the initiation of treatment were (41.94±24.19), (36.99±19.78), (34.30±20.62), (34.14±14.52), (36.64±23.61) and (104.65±50.16), (112.98±45.03), (118.43±45.00), (111.67±40.44), (109.55±27.54) pg/ml, respectively. (3) Bivariate correlation analysis results indicated that the plasma TREM-2 content was negatively correlated with the plasma levels of pro-inflammatory cytokines IL-6 and IL-8 (r = -0.224, P = 0.025; r = - 0.223, P = 0.026). ROC curve analysis showed that the mRNA levels of TREM-2 in PBMCs at various time points for prognostic evaluation of HBV-ACLF patients were 1d=0.667, 7d=0.757, 14d=0.979, 21d=0.986, and 28d= 0.993. The areas under the ROC curve of the TREM-2 content in the plasma at various time points were 1d=0.522, 7d=0.571, 14d=0.658, 21d=0.927, and 28d=0.994. Conclusion: TREM-2 mRNA expression in PBMC and TREM-2 content in plasma have a significant relationship to the prognosis of HBV-ACLF patients and may inhibit the liver inflammatory response by regulating the secretion of pro-inflammatory cytokines IL-6 and IL-8. Dynamic monitoring of TREM-2 expression in peripheral blood is favorable for evaluating the prognostic condition of HBV-ACLF patients.
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Insuficiencia Hepática Crónica Agudizada , Hepatitis B , Humanos , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/virología , Virus de la Hepatitis B , Interleucina-6/análisis , Interleucina-8/análisis , Leucocitos Mononucleares , Pronóstico , ARN Mensajero , Hepatitis B/tratamiento farmacológicoRESUMEN
Background and study aims: Glucocorticoid (GC) treatment for liver failure is controversial. This study sought to evaluate the efficacy and predictive factors of glucocorticoid therapy for hepatitis B virus-related acute-on-chronic liver failure (HBV- ACLF). Patients and methods: A total of 302 patients with HBV- ACLF were enrolled and categorized by treatment modality (GC vs. Control). Baseline characteristics, liver function, disease complications, and mortality were recorded. Univariate and multivariate analysis were used to identify predictive factors for HBV-ACLF-related mortality. Results: GC therapy significantly improved the 30- and 60-day mortality of HBV-ACLF patients (4.64% vs. 11.92%, P=0.022 and 16.56% vs. 25.83%, P=0.049 for the Control and GC groups, respectively) and GC was an independent prognostic factor for 30-day mortality (OR = 0.177, 95% CI 0.051-0.616, P = 0.007). However, enhanced survival was not associated with improved liver function. There were no significant differences in the incidence of complications (i.e., ascites, bacterial infection, encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding) between the GC and Control groups (P >0.05), except that fungal infection occurred with higher frequency in the GC group (P = 0.037). A significant improvement in the 30-day survival associated with GC therapy was observed among patients <40 years of age, a Model for End-stage Liver Disease (MELD) score of 25-35 or a CLIF- Consortium ACLF (CLIF-C ACLF) grade 0-1 (all P <0.05). Conclusions: GC therapy improved the short-term (30- and 60- day) mortality of patients with HBV-ACLF. This treatment may be of particular benefit to patients who are <40 years of age, have a MELD score of 25-35, or have a CLIF-C ACLF grade of 0-1. (Acta gastroenterol. belg., 2022, 85, 593-600).
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Insuficiencia Hepática Crónica Agudizada , Enfermedad Hepática en Estado Terminal , Hepatitis B , Humanos , Virus de la Hepatitis B , Glucocorticoides/uso terapéutico , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Insuficiencia Hepática Crónica Agudizada/complicaciones , Enfermedad Hepática en Estado Terminal/tratamiento farmacológico , Enfermedad Hepática en Estado Terminal/complicaciones , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Hepatitis B/complicacionesRESUMEN
BACKGROUND: Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are characterized by systemic inflammation and high mortality, but there is no effective clinical treatment. As a classic traditional Chinese medicine (TCM) formula, MaHuang-LianQiao-ChiXiaoDou decoction (MHLQD) has been used clinically for centuries to treat liver diseases. METHODS: The LPS/D-GalN-induced ALF mice model and the CCl4+LPS/D-GalN-induced ACLF mice model were used to observe the therapeutic effects of MHLQD on mice mortality, hepatocytes death, liver injury, and immune responses. RESULTS: MHLQD treatment significantly improved mice mortality. Liver injury and systemic and hepatic immune responses were also ameliorated after MHLQD treatment. Mechanistically, proteomic changes in MHLQD-treated liver tissues were analyzed and the result showed that the thrombogenic von Willebrand factor (VWF) was significantly inhibited in MHLQD-treated ALF and ACLF models. Histological staining and western blotting confirmed that VWF/RAP1B/ITGB3 signaling was suppressed in MHLQD-treated ALF and ACLF models. Furthermore, mice treated with the VWF inhibitor ADAMTS13 showed a reduced therapeutic effect from MHLQD treatment. CONCLUSIONS: Our study indicated that MHLQD is an effective herbal formula for the treatment of ALF and ACLF, which might be attributed to the protection of hepatocytes from death via VWF/RAP1B/ITGB3 signaling.