Objective To investigate the effects of YAP on the occurrence and progression of acute liver failure by regulating the ferroptosis pathway and its underlying mechanism. Methods A total of 20 8-week-old C57BL/6 mice were randomly divided into four groups: a control group, an acute liver failure model group, a YAP agonist XMU-MP-1 treatment group and a YAP inhibitor verteporfin treatment group, five mice for each group. HE staining was used to observe the pathological changes of hepatic inflammation and necrosis. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected by liver biochemistry. Iron (Fe), malondialdehyde (MDA), glutathione (GSH) determination kits were used to measure their levels in liver tissues of each group. The changes of hepatocyte mitochondrial in each group were observed by electron microscopy. Real time PCR and Western blot analysis were used to detect the mRNA and protein expressions of YAP, glutathione peroxidase 4 (GPX4) and 5-lipoxygenase (5-LOX). Results Compared with the control group, mice in the acute liver failure model group and the YAP inhibitor verteporfin treatment group showed severe liver tissue congestion with inflammatory cell infiltration and structural damage to hepatic lobules. Liver injury was alleviated in the XMU-MP-1 treatment group. With the occurrence of liver failure, plasma ALT and AST levels significantly increased, and liver function was improved in XMU-MP-1 treatment group. Electron microscopy showed that mitochondria in hepatocytes of mice with liver failure became smaller and bilayer membrane density increased, while mitochondria changes in the XMU-MP-1 group were alleviated. In addition, the acute liver failure model group showed an increase in Fe and MDA contents, decreased protein expressions of GPX4, and enhanced expression of 5-LOX, suggesting that ferroptosis was involved in acute liver failure in C57BL/6 mice. Ferroptosis was inhibited by activation of YAP. Conclusion Activation of YAP may ameliorate liver injury by inhibiting ferroptosis.
Animals ; Mice ; Ferroptosis ; Glutathione ; Liver Failure ; Liver Failure, Acute/drug therapy* ; Mice, Inbred C57BL ; Verteporfin ; YAP-Signaling Proteins/metabolism*

The three-day-old female infant was admitted to the hospital due to respiratory distress after birth. She was born premature at 36⁺² weeks gestational age. Prenatal ultrasound suggested abnormal development of the fetal liver vessels, and she had dyspnea that required respiratory support after birth. Chest X-ray indicated an enlarged cardiac silhouette, and cardiac ultrasound revealed enlargement of the right atrium and right ventricle. Diagnosis of hepatic hemangioma with arteriovenous fistula was confirmed through liver ultrasound and abdominal enhanced CT. At 19 days old, she underwent ligation of the hepatic artery under general anesthesia, which led to an improvement in cardiac function and she was subsequently discharged. Genetic testing revealed a mutation in the ACVRL1 gene, which was inherited from the mother. The article primarily introduces a case of neonatal heart failure caused by hepatic hemangioma with arteriovenous fistula, and multi-disciplinary diagnosis and treatment of this disease.
Female ; Humans ; Infant, Newborn ; Pregnancy ; Activin Receptors, Type II ; Arteriovenous Fistula/complications* ; Dyspnea ; Heart Failure/etiology* ; Hemangioma/complications* ; Liver

OBJECTIVE: Acute liver failure (ALF) is characterized by severe liver dysfunction, rapid progression and high mortality and is difficult to treat. Studies have found that sulforaphane (SFN), a nuclear factor E2-related factor 2 (NRF2) agonist, has anti-inflammatory, antioxidant and anticancer effects, and has certain protective effects on neurodegenerative diseases, cancer and liver fibrosis. This paper aimed to explore the protective effect of SFN in ALF and it possible mechanisms of action. METHODS: Lipopolysaccharide and D-galactosamine were used to induce liver injury in vitro and in vivo. NRF2 agonist SFN and histone deacetylase 6 (HDAC6) inhibitor ACY1215 were used to observe the protective effect and possible mechanisms of SFN in ALF, respectively. Cell viability, lactate dehydrogenase (LDH), Fe²⁺, glutathione (GSH) and malondialdehyde (MDA) were detected. The expression of HDAC6, NRF2, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11) were detected by Western blotting and immunofluorescence. RESULTS: Our results show that NRF2 was activated by SFN. LDH, Fe²⁺, MDA and ACSL4 were downregulated, while GSH, GPX4 and SLC7A11 were upregulated by SFN in vitro and in vivo, indicating the inhibitory effect of SFN on ferroptosis. Additionally, HDAC6 expression was decreased in the SFN group, indicating that SFN could downregulate the expression of HDAC6 in ALF. After using the HDAC6 inhibitor, ACY1215, SFN further reduced HDAC6 expression and inhibited ferroptosis, indicating that SFN may inhibit ferroptosis by regulating HDAC6 activity. CONCLUSION SFN has a protective effect on ALF, and the mechanism may include reduction of ferroptosis through the regulation of HDAC6. Please cite this article as: Zhang YQ, Shi CX, Zhang DM, Zhang LY, Wang LW, Gong ZJ. Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity. J Integr Med. 2023; 21(5): 464-473.
Humans ; Ferroptosis ; NF-E2-Related Factor 2/genetics* ; Liver Failure, Acute/drug therapy* ; Isothiocyanates/pharmacology* ; Glutathione ; Histone Deacetylase 6

Humans ; Child ; COVID-19/complications* ; Brain Diseases ; Myositis/complications* ; Kidney ; Liver Failure, Acute/complications* ; Acute Kidney Injury/complications*

Child ; Humans ; Liver Failure, Acute/therapy* ; Liver Transplantation/adverse effects*

OBJECTIVES: Gram-positive cocci is the main pathogen responsible for early infection after liver transplantation (LT), posing a huge threat to the prognosis of liver transplant recipients. This study aims to analyze the distribution and drug resistance of Gram-positive cocci, the risk factors for infections and efficacy of antibiotics within 2 months after LT, and to guide the prevention and treatment of these infections. METHODS: In this study, data of pathogenic bacteria distribution, drug resistance and therapeutic efficacy were collected from 39 Gram-positive cocci infections among 256 patients who received liver transplantation from donation after citizens' death in the Third Xiangya Hospital of Central South University from January 2019 to July 2022, and risk factors for Gram-positive cocci infection were analyzed. RESULTS: Enterococcus faecium was the dominant pathogenic bacteria (33/51, 64.7%), followed by Enterococcus faecalis (11/51, 21.6%). The most common sites of infection were abdominal cavity/biliary tract (13/256, 5.1%) and urinary tract (10/256, 3.9%). Fifty (98%) of the 51 Gram-positive cocci infections occurred within 1 month after LT. The most sensitive drugs to Gram-positive cocci were teicoplanin, tigecycline, linezolid and vancomycin. Vancomycin was not used in all patients, considering its nephrotoxicity. Vancomycin was not administered to all patients in view of its nephrotoxicity.There was no significant difference between the efficacy of daptomycin and teicoplanin in the prevention of cocci infection (P>0.05). Univariate analysis indicated that preoperative Model for End-Stage Liver Disease (MELD) score >25 (P=0.005), intraoperative red blood cell infusion ≥12 U (P=0.013) and exposure to more than 2 intravenous antibiotics post-LT (P=0.003) were related to Gram-positive cocci infections. Multivariate logistic regression analysis revealed that preoperative MELD score >25 (OR=2.378, 95% CI 1.124 to 5.032, P=0.024) and intraoperative red blood cell transfusion ≥ 12 U (OR=2.757, 95% CI 1.227 to 6.195, P=0.014) were independent risk factors for Gram-positive cocci infections after LT. Postoperative Gram-positive cocci infections were reduced in LT recipients exposing to more than two intravenous antibiotics post-LT (OR=0.269, 95% CI 0.121 to 0.598, P=0.001). CONCLUSIONS Gram-positive cocci infections occurring early after liver transplantation were dominated by Enterococcus faecalis infections at the abdominal/biliary tract and urinary tract. Teicoplanin, tigecycline and linezolid were anti-cocci sensitive drugs. Daptomycin and teicoplanin were equally effective in preventing cocci infections due to Gram-positive cocci. Patients with high preoperative MELD score and massive intraoperative red blood cell transfusion were more likely to suffer Gram-positive cocci infection after surgery. Postoperative Gram-positive cocci infections were reduced in recipients exposing to more than two intravenous antibiotics post-LT.
Humans ; Daptomycin/therapeutic use* ; Linezolid/therapeutic use* ; Teicoplanin/therapeutic use* ; Gram-Positive Cocci ; Liver Transplantation/adverse effects* ; Tigecycline/therapeutic use* ; End Stage Liver Disease/drug therapy* ; Gram-Positive Bacterial Infections/microbiology* ; Severity of Illness Index ; Anti-Bacterial Agents/pharmacology* ; Vancomycin/therapeutic use* ; Microbial Sensitivity Tests

Objective: To examine the clinical effect of auxiliary liver transplantation with ultra-small volume graft in the treatment of portal hypertension. Methods: Twelve cases of portal hypertension treated by auxiliary liver transplantation with small volume graft at Liver Transplantation Center,Beijing Friendship Hospital, Capital Medical University between December 2014 and March 2022 were studied retrospectively. There were 8 males and 4 females,aged 14 to 66 years. Model for end-stage liver disease scores were 1 to 15 points and Child scores were 6 to 11 points. The grafts was derived from living donors in 9 cases,from split cadaveric donors in 2 cases,from whole cadaveric liver of child in 1 case. The graft recipient body weight ratios of 3 cadaveric donor livers were 0.79% to 0.90%, and of 9 living donor livers were 0.31% to 0.55%.In these cases, ultra-small volume grafts were implanted. The survivals of patient and graft, complications, portal vein blood flow of residual liver and graft, abdominal drainage and biochemical indexes of liver function were observed. Results: All the grafts and patients survived. Complications included outflow tract torsion in 2 cases, acute rejection in 1 case, bile leakage in 1 case, and thyroid cancer at the later stage of follow-up in 1 case, all of which were cured. The torsion of outflow tract was attributed to the change of anastomotic angle after the growth of donor liver. After the improvement of anastomotic method, the complication did not recur in the later stage. There was no complication of portal hypertension. The measurement of ultrasonic portal vein blood flow velocity showed that the blood flow of residual liver decreased significantly in the early stage after operation, and maintained a very low blood flow velocity or occlusion in the long term after operation, and the blood flow of transplanted liver was stable. Conclusions: Auxiliary liver transplantation can implant ultra-small donor liver through compensation of residual liver. This method may promote the development of living donor left lobe donation and split liver transplantation. However, the auxiliary liver transplantation is complex, and it is difficult to control the complications. Therefore, this method is currently limited to centers that are skilled in living related liver transplantation and that have complete ability to monitor and deal with complications.
Male ; Child ; Female ; Humans ; Liver Transplantation/methods* ; End Stage Liver Disease/surgery* ; Retrospective Studies ; Living Donors ; Severity of Illness Index ; Neoplasm Recurrence, Local ; Liver/blood supply* ; Hypertension, Portal/surgery* ; Portal Vein ; Cadaver

Objective: To investigate the clinical efficacy of liver transplantation in the treatment of acute liver in children with NBAS gene deficiency disease and their outcome. Methods: This retrospective study enrolled children with NBAS gene deficiency who were admitted to the Children's Hospital of Fudan University for liver transplantation from January 2013 to June 2022. The clinical data were collected and analyzed. Medical literature published before June 2022 was searched with the keywords of "NBAS" "neuroblastoma amplified sequence recurrent" "acute liver failure" "SOPH syndrome" "short stature with optic nerve atrophy" "Pelger-Huët anomaly" in PubMed, China National Knowledge Infrastructure and Wanfang database. Results: Liver transplantation was performed in 3 patients (2 males and 1 female) with NBAS deficiency. All patients presented with fever-triggered recurrent acute liver failure. The genetic detection found compound heterozygous NBAS gene pathogenic variants in them. The total episodes of acute liver failure before liver transplantation were 11, 2, and 4 respectively, and the age at liver transplantation was 3.5, 2.3, and 2.0 years respectively. During liver transplantation, patient 1 was in the convalescent phase of acute liver failure, patient 2 was in the acute phase, presenting with hepatic encephalopathy (grade V) and respiratory failure, and patient 3 was considered to be in the acute phase. After liver transplantation, patient 1 recovered normal liver function within 1 month and had no liver transplantation-related complications. Patient 2 had secondary epilepsy, intellectual disability, movement disorder, and transiently elevated transaminases. Patient 3 died of severe infection within 1 month. There was no literature in Chinese, 6 in English, 8 NBAS-deficient patients who were treated with liver transplantation. Total 11 patients presented with fever-triggered recurrent acute liver failure. Their age at liver transplantation ranged from 0.9 to 5.0 years. Postoperative complications occurred in 3 patients. Until the last visit, they were followed up for 0.7 to 14.0 years. Total 2 patients died and the 9 surviving patients did not develop acute liver failure. Conclusions: Liver transplantation is effective for the treatment of acute liver failure associated with NBAS gene disease. However, postoperative complications of liver transplantation may occur. The timing of liver transplantation still needs further research.
Child ; Male ; Humans ; Female ; Infant ; Child, Preschool ; Retrospective Studies ; Neoplasm Proteins/genetics* ; Optic Atrophy/genetics* ; Pelger-Huet Anomaly/genetics* ; Liver Failure, Acute/complications*

Objective: To identify the predisposing factors, clinical characteristics, and risk factors of disease progression to establish a novel predictive survival model and evaluate its application value for hepatitis B virus-related acute-on-chronic liver failure. Methods: 153 cases of HBV-ACLF were selected according to the guidelines for the diagnosis and treatment of liver failure (2018 edition) of the Chinese Medical Association Hepatology Branch. Predisposing factors, the basic liver disease stage, therapeutic drugs, clinical characteristics, and factors affecting survival status were analyzed. Cox proportional hazards regression analysis was used to screen prognostic factors and establish a novel predictive survival model. The receiver operating characteristic curve (ROC) was used to evaluate predictive value with the Model for End-Stage Liver Disease (MELD) and the Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLF). Results: 80.39% (123/153) based on hepatitis B cirrhosis had developed ACLF. HBV-ACLF's main inducing factors were the discontinuation of nucleos(t)ide analogues (NAs) and the application of hepatotoxic drugs, including Chinese patent medicine/Chinese herbal medicine, non-steroidal anti-inflammatory drugs, anti-tuberculosis drugs, central nervous system drugs, anti-tumor drugs, etc. 34.64% of cases had an unknown inducement. The most common clinical symptoms at onset were progressive jaundice, poor appetite, and fatigue. The short-term mortality rate was significantly higher in patients complicated with hepatic encephalopathy, upper gastrointestinal hemorrhage, hepatorenal syndrome, and infection (P < 0.05). Lactate dehydrogenase, albumin, the international normalized ratio, the neutrophil-to-lymphocyte ratio, hepatic encephalopathy, and upper gastrointestinal bleeding were the independent predictors for the survival status of patients. The LAINeu model was established. The area under the curve for evaluating the survival of HBV-ACLF was 0.886, which was significantly higher than the MELD and CLIF-C ACLF scores (P < 0.05), and the prognosis was worse when the LAINeu score ≥ -3.75. Conclusion: Discontinuation of NAs and the application of hepatotoxic drugs are common predisposing factors for HBV-ACLF. Hepatic decompensation-related complications and infection accelerate the disease's progression. The LAINeu model can predict patient survival conditions more accurately.
Humans ; Hepatitis B virus ; Hepatic Encephalopathy/complications* ; Acute-On-Chronic Liver Failure/diagnosis* ; End Stage Liver Disease/complications* ; Severity of Illness Index ; Risk Factors ; ROC Curve ; Prognosis ; Retrospective Studies

Objective: To compare the safety and efficacy of transmesenteric vein extrahepatic portosystemic shunt (TEPS) and transjugular intrahepatic portosystemic shunt (TIPS) in the treatment of cavernous transformation of the portal vein (CTPV). Methods: The clinical data of CTPV patients with patency or partial patency of the superior mesenteric vein treated with TIPS or TEPS treatment in the Department of Vascular Surgery of Henan Provincial People's Hospital from January 2019 to December 2021 were selected. The differences in baseline data, surgical success rate, complication rate, incidence rate of hepatic encephalopathy, and other related indicators between TIPS and TEPS group were statistically analyzed by independent sample t-test, Mann-Whitney U test, and Chi-square test. Kaplan-Meier survival curve was used to calculate the cumulative patency rate of the shunt and the recurrence rate of postoperative portal hypertension symptoms in both groups. Results: The surgical success rate (100% vs. 65.52%), surgical complication rate (6.67% vs. 36.84%), cumulative shunt patency rate (100% vs. 70.70%), and cumulative symptom recurrence rate (0% vs. 25.71%) of the TEPS group and TIPS group were statistically significantly different (P < 0.05). The time of establishing the shunt [28 (2141) min vs. 82 (51206) min], the number of stents used [1 (12) vs. 2 (15)], and the length of the shunt [10 (912) cm vs. 16 (1220) cm] were statistically significant between the two groups (t = -3.764, -4.059, -1.765, P < 0.05). The incidence of postoperative hepatic encephalopathy in the TEPS group and TIPS group was 6.67% and 15.79% respectively, with no statistically significant difference (Fisher's exact probability method, P = 0.613). The pressure of superior mesenteric vein decreased from (29.33 ± 1.99) mmHg to (14.60 ± 2.80) mmHg in the TEPS group and from (29.68 ± 2.31) mmHg to (15.79 ± 3.01) mmHg in TIPS group after surgery, and the difference was statistically significant (t = 16.625, 15.959, P < 0.01). Conclusion: The best indication of TEPS is in CTPV patients with patency or partial patency of the superior mesenteric vein. TEPS improves the accuracy and success rate of surgery and reduces the incidence of complications.
Humans ; Portal Vein/surgery* ; Portasystemic Shunt, Transjugular Intrahepatic/methods* ; Hepatic Encephalopathy/etiology* ; Treatment Outcome ; Hypertension, Portal/complications* ; Retrospective Studies ; Gastrointestinal Hemorrhage/etiology*