OBJECTIVES: To explore the role of the cGAS-STING signaling pathway in the therapeutic mechanism of Liangxue Jiedu Huayu Formula (LXJDHYF) for acute-on-chronic liver failure (ACLF) in mice. METHODS: Thirty C57BL/6 mice were randomly divided into blank control group, model group, low- and high-dose LXJDHYF groups, and H151 (a specific cGAS-STING pathway inhibitor) group (n=6). In all but the control group, the mice were treated with CCl₄ to induce liver cirrhosis followed by intraperitoneal injections of lipopolysaccharide and D-amino galactose to establish mouse models of ACLF. After the treatments, the mouse livers were collected for HE and TUNEL staining, and serum levels of ALT, AST and TBil were determined. In bone marrow-derived macrophages (BMDMs) and liver tissues of ACLF mice, the expressions of cGAS-STING signaling pathway-related mRNAs including IFN‑β, ISG15, IL-6 and TNF-α were determined with RT-qPCR, and the phosphorylation levels of IRF3 and STING proteins were investigated using Western blotting. RESULTS: Compared with the mice in the model group, the LXJDHYF-treated mice exhibited milder hepatocyte necrosis and inflammatory cell infiltration in the liver with significantly reduced hepatocyte apoptosis. LXJDHYF treatment also significantly lowered serum levels of ALT, AST, TBil, IL-6 and TNF-α in ACLF mice and effectively suppressed the expressions of cGAS-STING signaling pathway-related mRNA in both the BMDMs and the liver tissues and the phosphorylation of IRF3 and STING proteins in the BMDMs. CONCLUSIONS LXJDHYF can significantly improve liver function and attenuate inflammation in ACLF mice possibly by inhibiting excessive activation of the cGAS-STING signaling pathway.
Animals ; Signal Transduction/drug effects* ; Mice ; Nucleotidyltransferases/metabolism* ; Mice, Inbred C57BL ; Acute-On-Chronic Liver Failure/etiology* ; Membrane Proteins/metabolism* ; Drugs, Chinese Herbal/therapeutic use* ; Liver/metabolism* ; Disease Models, Animal ; Interferon Regulatory Factor-3/metabolism* ; Interleukin-6/metabolism* ; Male

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

Patients with acute-on-chronic hepatitis B liver failure (HBV-ACLF) show high morbidity and mortality. Independent prognostic predictors of short-term HBV-ACLF mortality include the Child-Turcotte-Pugh (CTP) score, the model for end-stage liver disease (MELD) score, other MELD-based indices and the dynamic changes in these indices. The aims of this study were to evaluate the existing prognostic scores in a large cohort of HBV-ACLF patients and create a new predictive model. We retrospectively reviewed 392 HBV-ACLF patients from December 2008 to November 2011 and evaluated their 3-month survival. The predictive accuracy of CTP, MELD and MELD-based indices and the dynamic changes in the MELD-related scores (Δ scoring systems) upon admission and after two weeks of treatment were compared using the area under the receiver operating characteristic (ROC) curve method. Life-threatening factors and a series of bio-clinical parameters were studied by univariate and multivariate analyses. Among the existing scores, MELD had the best predictive ability. However, our new regression model provided an area under the curve of 0.930 ± 0.0161 (95% CI: 0.869 to 0.943), which was significantly larger than that obtained with the MELD score at admission and after two weeks of treatment as well as with the dynamic changes of the MELD score (0.819, 0.921, and 0.826, respectively) (Z=3.542, P=0.0004). In a large cohort of patients retrospectively reviewed for this study, our prognostic model was superior to the MELD score and is, therefore, a promising predictor of short-term survival in patients with HBV-ACLF.
Acute Disease ; Adult ; Chronic Disease ; Female ; Hepatitis B ; complications ; Humans ; Liver Failure ; etiology ; Male ; Middle Aged ; Prognosis

BACKGROUND/AIMS: Hepatitis-B-related acute-on-chronic liver failure has a poor prognosis. However, the advent of potent oral antiviral agents means that some patients can now recover with medical treatment. We aimed to identify the prognostic factors for hepatitis-B-related acute-on-chronic liver failure including the initial as well as the dynamically changing clinical parameters during admission. METHODS: Sixty-seven patients were retrospectively enrolled from 2003 to 2012 at Samsung Medical Center. The patients were classified into three categories: Recovery group (n=23), Liver transplantation group (n=28), and Death group (n=16). The Liver transplantation and Death groups were combined into an Unfavorable prognosis group. We analyzed the prognostic factors including the Model for End-Stage Liver Disease (MELD) scores determined at 3-day intervals. RESULTS: A multivariable analysis showed that the unfavorable prognostic factors were a high initial MELD score (> or =28) (odds ratio [OR] =6.64, p=0.015), moderate-to-severe ascites at admission (OR=6.71, P=0.012), and the aggravation of hepatic encephalopathy during hospitalization (> or =grade III) (OR=15.41, P=0.013). Compared with the baseline level, significant reductions in the MELD scores were observed on the 7th day after admission in the Recovery group (P=0.016). CONCLUSIONS: Dynamic changes in clinical parameters during admission are useful prognostic factors for hepatitis-B-related acute-on-chronic liver failure.
Acute-On-Chronic Liver Failure/*diagnosis/drug therapy/etiology ; Adult ; Aged ; Antibodies, Monoclonal, Murine-Derived/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Antiviral Agents/therapeutic use ; Cyclophosphamide/therapeutic use ; DNA, Viral/analysis ; Doxorubicin/therapeutic use ; Female ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/complications/*diagnosis/drug therapy ; Hospitalization ; Humans ; Liver Transplantation ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Prednisone/therapeutic use ; Prognosis ; Retrospective Studies ; Severity of Illness Index ; Vincristine/therapeutic use ; Young Adult

Lamotrigine is an anticonvulsant drug used to treat partial and generalized seizure disorders. Hypersensitivity to lamotrigine usually causes mild symptoms such as fever, rash, and slight invasion of internal organs. However, a 33-year-old male patient who was admitted with Stevens-Johnson syndrome after taking lamotrigine for 15 days experienced hepatic failure and died 5 days after admission. This case demonstrates the importance of realizing that lamotrigine can lead to fatal hepatic failure, and that tests for the normal liver function should be performed when administering lamotrigine.
Adult ; Alanine Transaminase/blood ; Anticonvulsants/*adverse effects/therapeutic use ; Aspartate Aminotransferases/blood ; Drug Hypersensitivity/complications/*diagnosis ; Humans ; Liver/enzymology/metabolism ; Liver Failure/*etiology ; Male ; Stevens-Johnson Syndrome/diagnosis/drug therapy ; Triazines/*adverse effects/therapeutic use

BACKGROUND/AIMS: A revised classification system for renal dysfunction in patients with cirrhosis was proposed by the Acute Dialysis Quality Initiative and the International Ascites Club Working Group in 2011. The aim of this study was to determine the prevalence of renal dysfunction according to the criteria in this proposal. METHODS: The medical records of cirrhotic patients who were admitted to Konkuk University Hospital between 2006 and 2010 were reviewed retrospectively. The data obtained at first admission were collected. Acute kidney injury (AKI) and chronic kidney disease (CKD) were defined using the proposed diagnostic criteria of kidney dysfunction in cirrhosis. RESULTS: Six hundred and forty-three patients were admitted, of whom 190 (29.5%), 273 (42.5%), and 180 (28.0%) were Child-Pugh class A, B, and C, respectively. Eighty-three patients (12.9%) were diagnosed with AKI, the most common cause for which was dehydration (30 patients). Three patients had hepatorenal syndrome type 1 and 26 patients had prerenal-type AKI caused by volume deficiency after variceal bleeding. In addition, 22 patients (3.4%) were diagnosed with CKD, 1 patient with hepatorenal syndrome type 2, and 3 patients (0.5%) with AKI on CKD. CONCLUSIONS: Both AKI and CKD are common among hospitalized cirrhotic patients, and often occur simultaneously (16.8%). The most common type of renal dysfunction was AKI (12.9%). Diagnosis of type 2 hepatorenal syndrome remains difficult. A prospective cohort study is warranted to evaluate the clinical course in cirrhotic patients with renal dysfunction.
Acute Kidney Injury/*epidemiology/etiology/mortality ; Adult ; Aged ; Cohort Studies ; Female ; Hospital Mortality ; Humans ; Kidney Failure, Chronic/*epidemiology/etiology/mortality ; Liver Cirrhosis/complications/*diagnosis ; Male ; Middle Aged ; Prevalence ; Prospective Studies ; Severity of Illness Index ; Survival Rate

PURPOSE: Due to the seroepidemiological shift in hepatitis A (HA), its severity, mortality, and complications have increased in recent years. Thus, the aim of this study was to identify predictive factors associated with poor prognosis among patients with HA. MATERIALS AND METHODS: A total of 304 patients with HA admitted to our institution between July 2009 and June 2011 were enrolled consecutively. Patients with complications defined as acute liver failure (ALF) were evaluated, and mortality was defined as death or liver transplantation. RESULTS: The mean age of patients (204 males, 100 females) was 32 years. Eighteen (5.9%) patients had progressed to ALF. Of the patients with ALF, 10 patients (3.3%) showed spontaneous survival while 8 (2.6%) died or underwent liver transplantation. Multivariate regression analysis showed that Model for End-Stage Liver Disease (MELD) and systemic inflammatory response syndrome (SIRS) scores were significant predictive factors of ALF. Based on receiver operating characteristics (ROC) analysis, a MELD > or =23.5 was significantly more predictive than a SIRS score > or =3 (area under the ROC: 0.940 vs. 0.742, respectively). In addition, of patients with a MELD score > or =23.5, King's College Hospital criteria (KCC) and SIRS scores were predictive factors associated with death/transplantation in multivariate analysis. CONCLUSION: MELD and SIRS scores > or =23.5 and > or =3, respectively, appeared to be related to ALF development. In addition, KCC and SIRS scores > or =3 were valuable in predicting mortality of patients with a MELD > or =23.5.
Adult ; Female ; Hepatitis A/*complications ; Humans ; Liver Failure, Acute/*etiology/*mortality/pathology ; Male ; Multivariate Analysis ; Prognosis ; Prospective Studies ; ROC Curve ; Systemic Inflammatory Response Syndrome/complications

BACKGROUND/AIMS: The dose of mycophenolate mofetil (MMF) has been reduced in Asia due to side effects associated with the conventional fixed dose of 2-3 g/day. We aimed to determine the pharmacokinetics of a reduced dose of MMF and to validate its feasibility in combination with tacrolimus in living-donor liver transplantation (LDLT). METHODS: Two sequential studies were performed in adult LDLT between October 2009 and 2011. First, we performed a prospective pharmacokinetic study in 15 recipients. We measured the area under the curve from 0 to 12 hours (AUC0-12) for mycophenolic acid at postoperative days 7 and 14, and we performed a protocol biopsy before discharge. Second, among 215 recipients, we reviewed 74 patients who were initially administered a reduced dose of MMF (1.0 g/day) with tacrolimus (trough, 8-12 ng/mL during the first month, and 5-8 ng/mL thereafter), with a 1-year follow-up. We performed protocol biopsies at 2 weeks and 1 year post-LDLT. RESULTS: In the first part of study, AUC0-12 was less than 30 mgh/L in 93.3% of cases. In the second, validating study, 41.9% of the recipients needed dose reduction or cessation due to side effects within the first year after LDLT. At 12 months post-LDLT, 17.6% of the recipients were administered a lower dose of MMF (0.5 g/day), and 16.2% needed permanent cessation due to side effects. The 1- and 12-month rejection-free survival rates were 98.6% and 97.3%, respectively. CONCLUSIONS: A reduced dose of MMF was associated with low blood levels compared to the existing recommended therapeutic range. However, reducing the dose of MMF combined with a low level of tacrolimus was feasible clinically, with an excellent short-term outcome in LDLT.
Adult ; Aged ; Area Under Curve ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Gastrointestinal Diseases/etiology ; Graft Rejection/prevention & control ; Humans ; Immunosuppressive Agents/blood/*pharmacokinetics ; Leukopenia/etiology ; Liver/pathology ; Liver Failure/*therapy ; *Liver Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/adverse effects/*analogs & derivatives/blood/pharmacokinetics ; ROC Curve ; Retrospective Studies ; Tacrolimus/therapeutic use ; Tissue Donors

OBJECTIVETo compare the clinical values of the model for end-stage liver disease (MELD)-Na scoring system and the Child-Turcotte-Pugh (CTP) scoring system for predicting the short-term prognosis of acute-on-chronic hepatitis B liver failure.

METHODSA total of 339 patients with acute-on-chronic hepatitis B liver failure and admitted to the Eighth People's Hospital of Guangzhou and Nanfang Hospital of Southern Medical University between January 2010 and December 2012 were included in this retrospective analysis. The short-term predictive values of MELD-Na and CTP scores were compared for this patient population.

RESULTSThe mean MELD-Na score in the advanced stage of liver failure was significantly higher than those in the early and middle stages, respectively (both P less than 0.01). The mean MELD-Na score in the middle stage of liver failure was also significantly higher than that in the early stage (P less than 0.01). In contrast, the mean CTP scores for the three stages of liver failure were not significantly different (all P more than 0.05). The MELD-Na score showed a stronger correlation with the stage of liver failure (rs =0.485, P less than 0.01) than did the CTP score (rs =0.306, P less than 0.01). The short-term mortality rates were significantly different for the three stages of liver failure (P less than 0.01). The mean MELD-Na score of the death group was significantly higher than that of the survival group (P less than 0.01). The CTP scores, however, were not significantly different between the death and survival groups (P more than 0.05).The short-term mortality rate of liver failure was significantly higher for patients with increased scores for the MELD-Na and CTP systems (both P less than 0.01). The areas under the curve of the MELD-Na and CTP scores were 0.813 and 0.823, respectively. The MELD-Na and CTP score have similar predictive values (P more than 0.05).

CONCLUSIONThe MELD-Na scoring system is slightly superior to the CTP scoring system for predicting short-term prognosis of acute-on-chronic hepatitis B liver failure.The predictive value may improve for both the MELD-Na score and the CTP score when combined with expert clinical practice and experience.

Acute-On-Chronic Liver Failure ; etiology ; Hepatitis B ; Hepatitis B, Chronic ; complications ; Humans ; Prognosis ; Retrospective Studies ; Sodium

OBJECTIVETo investigate the clinical features and mechanisms of hepatitis B virus (HBV) reactivation induced by chemotherapy or immunosuppressive therapy and subsequent fulminant hepatic failure (FHF) in patients with autoimmune diseases.

METHODSSeven cases of FHF related to HBV reactivation were retrospectively assessed. All patients had been confirmed as hepatitis B e antigen (HBeAg) seronegative and had undergone glucocorticoid-based therapy to manage primary diseases, including nephrotic syndrome (2 cases), polycystic kidney disease combined with chronic nephritis (1 case), conditions following kidney transplantation (1 case), lymphadenoma (1 case), idiopathic thrombocytopenic purpura (1 case), and angitis (1 case). Levels of sero-markers of HBV and HBV DNA were recorded. Serum samples from patients were respectively applied to HepG2.2.15 and HepG2 cell lines in order to investigate the effects on cell proliferation (by MTT assay) and apoptosis (by Hoechst 33342 staining assay). Intergroup differences were statistically assessed by the t-test.

RESULTSFor all patients, the initial clinical signs of hepatic failure emerged at 4 to 11 months after receipt of the glucocorticoid treatment. At the time of hepatic failure, HBeAg seropositivity was detected in 4 patients, including one patient who also showed seropositivity for the hepatitis B surface antibody (HBsAb). All 7 patients showed high levels of HBV DNA when the hepatitis condition flared. Neither remedial antiviral treatments nor internal medicine comprehensive treatments, including therapeutic plasma exchange, were effective in any of these cases. The duration from clinical signs onset to death ranged from 24 to 47 days. Treatment of HepG2.2.15 and HepG2 cells with serum samples from patients with FHF showed a dosage-effect relationship of the serum concentration on the cellular proliferation inhibition rate, with the serum of patients with FHF having more severe inhibiting effects on the HepG2.2.15 cells than on the HepG2 cells. The HepG2.2.15 cells showed a greater tendency towards apoptosis upon treatment with serum samples from patients with FHF, compared to the HepG2 cells.

CONCLUSIONHBV reactivation induced by chemotherapy or immunosuppressive therapy is a problem currently encountered in the management of malignancies or rheumatic autoimmune disease patients. It is critical to verify HBV status prior to initiation of these treatment strategies so that appropriate antiviral prophylaxis may be administered, so as to reduce the risk of HBV reactivation and subsequent repression of cell proliferation and apoptosis that can promote development of FHF and increase a patient's risk of death.

Adult ; Aged ; Apoptosis ; Autoimmune Diseases ; complications ; Cell Proliferation ; Female ; Glucocorticoids ; adverse effects ; therapeutic use ; Hep G2 Cells ; Hepatitis B ; complications ; virology ; Hepatitis B virus ; drug effects ; Humans ; Liver Failure ; etiology ; virology ; Male ; Middle Aged ; Retrospective Studies ; Virus Activation ; drug effects