RATIONALE & OBJECTIVE:Evidence is limited regarding the associations of nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) with the development of nephrolithiasis. This study assessed the associations of NAFLD and MAFLD with the risk of incident nephrolithiasis using data from 2 cohort studies conducted in the People's Republic of China and the United Kingdom. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:26,490 participants without nephrolithiasis at baseline in the Tianjin Chronic Low-grade Systemic Inflammation and Health Cohort Study (TCLSIH) and 294,577 participants in the UK Biobank. EXPOSURE:Fatty liver diagnosed by abdominal ultrasonography in the TCLSIH and by the Hepatic Steatosis Index in the UK Biobank. NAFLD and MAFLD were defined according to standard clinical criteria in both cohorts. OUTCOME:Nephrolithiasis was confirmed by ultrasonography in the TCLSIH and identified through ICD-10 and OPCS-4 in the UK Biobank. ANALYTICAL APPROACH:Cox proportional hazards regression analysis was used to assess the relationship between exposures and incident nephrolithiasis. RESULTS:The TCLSIH and the UK Biobank recorded 806 and 2,743 new cases of nephrolithiasis during a median follow-up period of 4 and 12 years, respectively. Participants in both cohorts showed a significantly increased risk of nephrolithiasis in the setting of NAFLD (TCLSIH: HR, 1.69 [95% CI, 1.46-1.95]; UK Biobank: HR, 1.66 [95% CI, 1.53-1.79]) and MAFLD (TCLSIH: HR, 1.79 [95% CI, 1.55-2.08]; UK Biobank: HR, 1.54 [95% CI, 1.42-1.66]) after multivariable adjustments. LIMITATIONS:Observational nature limits causal inferences; generalizability limited outside of the cohorts studied; limited diagnostic approaches to detect nephrolithiasis; unavailability of stone composition data. CONCLUSIONS:Both NAFLD and MAFLD are associated with a higher risk of nephrolithiasis. The results suggest that NAFLD/MAFLD and their associated metabolic conditions may represent modifiable risk factors for nephrolithiasis. PLAIN-LANGUAGE SUMMARY:Evidence on the association between nonalcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD) and the risk of nephrolithiasis remains limited. In this study, we assessed whether NAFLD or MAFLD were associated with an increased risk of developing nephrolithiasis by analyzing data from 2 large prospective cohorts in the People's Republic of China and the United Kingdom. Our findings demonstrated that individuals with NAFLD or MAFLD had a significantly higher risk of incident nephrolithiasis later in life. This increased risk remained consistent across different age and sex groups. Our findings underscore the importance of liver health as a potential risk factor for nephrolithiasis.

BACKGROUND:HBV, which contributes to liver fibrosis and HCC, is associated with autophagy and epithelial-mesenchymal transition (EMT). However, the relationship between HBV infection, autophagy, and EMT remains unknown. METHODS:In this study, we used HBV cell lines (HepAD38, Huh7.5.1-NTCP) to evaluate this relationship. RESULTS:HBV replication or infection promoted autophagy, EMT, and liver fibrogenesis. HBV-induced EMT/fibrogenesis was dependent on autophagy. HBV X and HBV core (C) were each involved during this process. TGF-β1 partially participated in HBV-induced autophagy/EMT/fibrosis. c-Jun N-terminal kinase (JNK) expression was increased in HepAD38 cells, HBV-X (HBV-C)-transfected Huh7.5.1 cells, and HBV-infected Huh7.5.1-NTCP cells. JNK silencing attenuated HBV-induced autophagy and EMT/fibrosis signaling as well. Moreover, overexpression of HBV-X(C) and augmentation of autophagy were shown to promote pJNK expression. Finally, we confirmed an HBV-JNK-autophagy-EMT/fibrosis signaling pathway in a primary human hepatocyte model. CONCLUSIONS:In conclusion, HBV induces autophagy through JNK, thus triggering downstream EMT and fibrogenesis signaling pathways. These findings suggest that JNKs could be potential targets for the treatment of HBV-related liver diseases.

Hepatitis B is mostly a chronic, progressive disease that, if not treated promptly and effectively, can slowly progress to cirrhosis, liver failure, or hepatocellular carcinoma. Therefore, antiviral therapy, i.e., a "complete therapy" strategy, should be started as long as the virus is positive. Immediate antiviral treatment is not recommended for infected patients who are only in the immune-tolerant phase, mainly because of the milder conditions and poor antiviral therapy efficacy, according to antiviral indications in China's Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Version). The relevant issues of why hepatitis B virus infection in the immune-tolerant phase is the last mile of "complete therapy," with an emphasis on the disease’s characteristics and antiviral treatment strategies, are discussed here.

Background and Aims:Necroptosis is critical for regulating intestinal epithelial cells (IECs). Butyric acid (BA), produced during intestinal microbial metabolism, protects the intestinal epithelial barrier. However, whether necroptosis occurs in IECs during liver cirrhosis and whether sodium butyrate (NaB) can regulate necroptosis have not yet been reported. In this study, we aimed to investigate whether IECs undergo necroptosis in cirrhosis and whether NaB can regulate necroptosis and the related regulatory mechanisms. Methods:Serum levels of RIPK3, MLKL, and Zonulin, as well as fecal BA levels, were measured and correlated in 48 patients with liver cirrhosis and 20 healthy controls. A rat model of liver cirrhosis was established, and NaB was administered. The expressions of MLKL, p-MLKL, and tight junction proteins were measured. We conducted an in vitro investigation of the effect of NaB on necroptosis in the HT29 cell line. Results:Serum levels of RIPK3, MLKL, and Zonulin in the liver cirrhosis group were higher, while fecal BA levels were lower than those in the control group. Zonulin levels were positively correlated with RIPK3 and MLKL levels, while fecal BA levels were negatively correlated with serum MLKL levels, but not with RIPK3 levels. NaB reduced the mRNA and protein expression of MLKL but had no effect on RIPK1 and RIPK3 in vitro. Rescue experiments demonstrated that NaB inhibited necroptosis through E2F1-mediated regulation of MLKL. Conclusions:NaB alleviates intestinal mucosal injury and reduces necroptosis in IECs in liver cirrhosis. It also inhibits the necroptosis of IECs and protects the intestinal barrier by reducing E2F1 expression and downregulating MLKL expression levels. These results can be employed to develop a novel strategy for treating complications arising from liver cirrhosis.

Abstract Background Hepatitis B virus (HBV) infection can cause thrombocytopenia through its effects on hematopoiesis, but the mechanisms underlying this process are still unclear. The process of platelet generation encompasses multiple stages, among these stages, the differentiation of mature megakaryocytes plays a pivotal role in platelet production. Objective In this study, we investigated the impact of HBV on the differentiation of mature megakaryocytes and its molecular mechanism. Methods Different doses of HBV virus solution extracted from HepAD38 cells were co-cultured with hematopoietic stem cells isolated from fresh, full-term healthy maternal cord blood through magnetic bead sorting. The study aimed to assess the variances in megakaryocyte differentiation and maturation after HBV infection. Furthermore, Label-free quantitative proteomics was employed to analyze the differential proteins during the mature megakaryocyte stages pre- and post-HBV infection, with a focus on elucidating their respective molecular mechanisms. Results Through comparison, it was discovered that HBV could impede the differentiation process of fully developed megakaryocytes. Specifically, during the maturation stage of megakaryocytes, HBV had the ability to hinder cell DNA polyploidization as well as the formation of cytoskeletal proteins. Furthermore, its suppressive effect was more pronounced in the later stages of differentiation, consequently leading to impaired platelet production. Proteomic analysis revealed noteworthy disparities in UBE4B protein levels within mature megakaryocytes after HBV infection. Upon transfection with lentivirus and subsequent knockdown of UBE4B in mature megakaryocytes, a noticeable alleviation of HBV's inhibitory impact on mature megakaryocytes was observed, accompanied by regulation of p53 and ERK1/2 expression and phosphorylation in the cells. Conclusion HBV can upregulate the expression of UBE4B, inhibit the expression and phosphorylation of p53, enhance the expression and phosphorylation of ERK1/2, suppress the differentiation of mature megakaryocytes, thereby leading to platelet production disorders.

Liver fibrosis is a pathological condition characterized by replacement of normal liver tissue with scar tissue, and also the leading cause of liver-related death worldwide. During the treatment of liver fibrosis, in addition to antiviral therapy or removal of inducers, there remains a lack of specific and effective treatment strategies. For thousands of years, Chinese herbal medicines (CHMs) have been widely used to treat liver fibrosis in clinical setting. CHMs are effective for liver fibrosis, though its mechanisms of action are unclear. In recent years, many studies have attempted to determine the possible mechanisms of action of CHMs in treating liver fibrosis. There have been substantial improvements in the experimental investigation of CHMs which have greatly promoted the understanding of anti-liver fibrosis mechanisms. In this review, the role of CHMs in the treatment of liver fibrosis is described, based on studies over the past decade, which has addressed the various mechanisms and signaling pathways that mediate therapeutic efficacy. Among them, inhibition of stellate cell activation is identified as the most common mechanism. This article provides insights into the research direction of CHMs, in order to expand its clinical application range and improve its effectiveness.

慢性乙型肝炎(慢乙肝)是我国最主要的慢性肝病,一般人群HBsAg阳性率仍然高达5％～6％,慢乙肝患者大约还有7000万～8400万.如果没有及时发现、早期诊断并给予规范的抗病毒治疗,疾病会隐匿进展,最终将发展为肝硬化、肝细胞癌或出现肝衰竭而导致死亡.

Timely and effective antiviral therapy can prevent or delay the progression of the disease to cirrhosis, liver failure, or hepatocellular carcinoma in patients with chronic hepatitis B. Antiviral therapy indications are constantly expanding, and eventually it will be manageable to treat viral positives based on the new understanding of the disease progression and the changes in the definition of abnormal values in liver function tests.

Objective: To prospectively explore the treatment strategies for clinical difficulties in patients with hyperviremia HBeAg-positive chronic hepatitis B with incomplete response to first-line nucleos(t)ide analogues (NAs). Methods: Patients with hyperviremia HBeAg-positive chronic hepatitis B were treated with first-line NAs, including entecavir, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) for 48 weeks or more. Tenofovir amibufenamide (TMF) or TAF therapy was changed when HBV DNA remained positive and then divided into a TMF group and a TAF group. Clinical efficacy of treatment was evaluated at 24 and 48 weeks, including HBV DNA undetectable rates and virological and serological responses in both patient groups. Results: In the TMF group and the TAF groups, 30 and 26 cases completed 24-week follow-up, while 18 and 12 cases completed 48-week follow-up. There were no statistically significant differences in baseline HBV DNA, HBsAg, and HBeAg levels between the two groups before switching to TMF/TAF therapy (P > 0.05). At 24 weeks of treatment, 19 (19/30, 63.33%) cases in the TMF group had HBV DNA negative conversion, while 14 (14/26, 53.85%) cases in the TAF group had HBV DNA negative conversion (P > 0.05). Among the patients who completed 48 weeks of follow-up, 15 (15/18, 83.33%) cases in the TMF group and 7 (7/12, 58.33%) cases in the TAF group had negative HBV DNA tests (P > 0.05). The changes in HBsAg and HBeAg levels between the two groups of patients at 24 and 48 weeks of treatment were not statistically significant compared to baseline (P > 0.05). Conclusion: TMF is effective in treating patients with hyperviremia HBeAg-positive CHB with an incomplete response to first-line NAs treatment, but there is no significant difference compared to TAF.

Hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection accelerates liver fibrosis progression compared with HBV or HCV monoinfection. Octamer binding transcription factor 4 (OCT4) and Nanog are direct targets of the profibrogenic TGF-β1 signaling cascade. We leveraged a coculture model to monitor the effects of HBV and HCV coinfection on fibrogenesis in both sodium taurocholate cotransporting polypeptide-transfected Huh7.5.1 hepatoma cells and LX2 hepatic stellate cells (HSCs). We used CRISPR-Cas9 to knock out OCT4 and Nanog to evaluate their effects on HBV-, HCV-, or TGF-β1-induced liver fibrogenesis. HBV/HCV coinfection and HBx, HBV preS2, HCV Core, and HCV NS2/3 overexpression increased TGF-β1 mRNA levels in sodium taurocholate cotransporting polypeptide-Huh7.5.1 cells compared with controls. HBV/HCV coinfection further enhanced profibrogenic gene expression relative to HBV or HCV monoinfection. Coculture of HBV and HCV monoinfected or HBV/HCV coinfected hepatocytes with LX2 cells significantly increased profibrotic gene expression and LX2 cell invasion and migration. OCT4 and Nanog guide RNA independently suppressed HBV-, HCV-, HBV/HCV-, and TGF-β1-induced α-SMA, TIMP-1, and Col1A1 expression and reduced Huh7.5.1, LX2, primary hepatocyte, and primary human HSC migratory capacity. OCT4/Nanog protein expression also correlated positively with fibrosis stage in liver biopsies from patients with chronic HBV or HCV infection. In conclusion, HBV and HCV independently and cooperatively promote liver fibrogenesis through a TGF-β1-induced OCT4/Nanog-dependent pathway.

Alanine aminotransferase (ALT) is a common clinical indicator of liver inflammation. The current Chinese guidelines for the management of chronic hepatitis B (CHB) recommend antiviral treatment for patients with detectable hepatitis B virus (HBV) DNA and persistent ALT levels (ALTs) exceeding the upper limit of normal. However, it has been recently reported that patients with chronic HBV infection, especially HBeAg-negative patients with persistently normal ALTs, may have liver biopsy findings of significant inflammation and fibrosis. For HBeAg-negative patients with chronic HBV infection and normal ALTs, many controversial questions have been asked. To treat or not? When to initiate the treatment? Which drug is appropriate? In this review, we summarize the available data on the management of HBeAg-negative patients with chronic HBV infection and normal ALTs with the aim of improving the current clinical management.

OBJECTIVE:To investigate the correlations of Helicobacter pylori (HP) with liver function, inflammatory factors and serum levels of forkhead box P3 (FoxP3) and retinoic acid receptor-related orphan receptor gamma-t (RORγt) in patients with hepatitis B cirrhosis (HBC).PATIENTS AND METHODS:A total of 60 HBC patients were divided into HBC group (n=30) and HP-infected HBC group (HP&HBC group, n=30). QRT-PCR was conducted to determine the messenger ribonucleic acid (mRNA) levels of FoxP3 and RORγt in serum samples. ELISA was applied to measure the levels of relevant inflammatory factors. Besides, immunohistochemical staining was conducted to detect positive expressions of FoxP3 and RORγt in liver tissues of patients in the two groups.RESULTS:No significant differences in gender, drinking, smoking, diabetes and age were found between HBC group and HP&HBC group (p>0.05). Globulin and albumin levels were comparable between the two groups (p>0.05). Liver function indexes, including ALT, AST and TBIL were higher in HP&HBC group than those in HBC group (p<0.05). The HBV-DNA level was lower in HBC group in comparison with that in HP&HBC group. The interferon-gamma (IFN-γ) level was remarkably higher in HBC group than that in HP&HBC group (p<0.01), and the levels of interleukin (IL)-6, IL-10, IL-17 and transforming growth factor (TGF)-β1 were notably lower in HBC group in comparison with those in HP&HBC group (p<0.01). Additionally, the mRNA levels of FoxP3 and RORγt in HBC group were distinctly lower than those in HP&HBC group (p<0.01). The mRNA levels of FoxP3 and RORγt were positively related to those of IL-6, IL-10, IL-17, and TGF-β1, and negatively associated with IFN-γ level. Immunohistochemical results indicated that positive expression rates of FoxP3 and RORγt in the liver tissues were approximately 50% in HP&HBC group and B. Zhao, Q.-J. Sheng, Y. Qin, X.-L. Wang, H. Zhao, N. Zhaowere 15% in HBC group, and the difference was statistically significant (p<0.05).CONCLUSIONS:Expression levels of FoxP3 and RORγt in serum and liver tissues are elevated in HP-infected HBC patients, and inflammatory factors are correlated with their expressions, suggesting the aggravated liver damage.

Pregnancy-related liver disease is a group of severe diseases that usually resulting in worsening clinical outcome in pregnant women and fetuses. Therefore, diagnosis and treatment at early-stage are essential. This paper reviews the early-stage clinical features, pathogenesis, diagnosis and treatment key points of common pregnancy-related liver diseases such as hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, hemolysis, elevated liver enzymes and low platelet syndrome, and acute fatty liver of pregnancy, in order to help clinicians, improve their understanding of pregnancy-related liver disease.

Hepatitis B virus (HBV) is a kind of hepatotropic DNA virus. The main target organ is liver, except for liver, HBV has been found in a variety of extrahepatic tissues, such as kidney, thyroid, pancreas, bone marrow, etc. HBV can cause severe complications by invading these tissues. Among them, pancytopenia is one of the common complications, especially thrombocytopenia that causes life-threatening bleeding. However, the mechanism of thrombocytopenia is unclear and the treatment is extremely difficult. It has been confirmed that HBV has a close relationship with platelets. HBV can directly infect bone marrow, inhibit platelet production, and accelerate platelet destruction by activating monocyte-macrophage system and immune system. While platelets act as a double-edged sword to HBV. On one hand, the activated platelets can degranulate and release inflammatory mediators to help clear the viruses. Furthermore, platelets can provide anti-fibrotic molecules to improve liver functions and reduce hepatic fibrosis. On the other hand, platelets can also cause negative effects. The infected platelets collect HBV-specific CD8+ T cells and nonspecific inflammatory cells into liver parenchyma, inducing chronic inflammation, liver fibrosis and hepatic carcinoma. This article explores the interaction between HBV infection and platelets, providing a theoretical basis for clinical treatment of thrombocytopenia and severe hemorrhage caused by HBV infection.

Background: Long noncoding RNAs (lncRNAs) have emerged as gene regulators in various cancers, including hepatocellular carcinoma (HCC). However, the biological roles and mechanisms of many lncRNAs in HCC tumorigenesis remain unknown. Aim: To identify novel lncRNAs associated with proliferation and metastasis in HCC. Methods: Expression profiles of lncRNAs were analyzed in HCC using two GSE datasets (GSE94660 and GSE104310). Functional studies were performed, including cell proliferation, colony formation, wound healing, and Transwell assays. Fluorescence in-situ hybridization (FISH), tandem mass tag (TMT) analyses, parallel reaction monitoring (PRM), and rescue assays were performed to evaluate the mechanisms underlying the effects of RP4-694A7.2. Results: RP4-694A7.2 levels were higher in HCC tissues than in normal liver tissues in published GSE datasets and were elevated in HCC cell lines. Cell function assays revealed that RP4-694A7.2 promotes cell proliferation, invasion, and migration. Furthermore, RP4-694A7.2 was primarily found to be located in the cytoplasm by FISH assay. Then, TMT assay was performed to predict proteins associated with RP4-694A7.2, and 28 cytoplastic proteins were identified by PRM. Finally, phosphoserine aminotransferase 1 (PSAT1) was found to be regulated by RP4-694A7.2 to modulate growth and metastasis in HCC cells using a rescue assay. Conclusions: These results suggested that RP4-694A7.2 promotes HCC cell proliferation and metastasis via PSAT1, providing a candidate therapeutic target for further research.

新冠疫情给全球带来了深远的影响,同时也加速中国的高等教育发生了重大的变革.在这样一种新发传染病全球大流行的背景下,笔者对中国高等医学教育传染病教学面临的挑战和发展机遇进行了深入的思考.文章对传染病教学的现状和面临的困境,疫情对传染病教学地位、教学目标、教学方式、教学内容等的影响,以及对传染病教学思政教育内容的影响,进行了详细的阐述.

Objective: To analyze, explore and evaluate the clinical characteristics, abnormal thyroid function and follow-up of anti-hyperthyroidism treatment mode in patients with hyperthyroidism (commonly abbreviated as HT) combined with liver injury. Methods: The clinical data of patients with hyperthyroidism combined with liver injury were retrospectively analyzed, and then patients were divided into treated and untreated group according to whether they received anti-hyperthyroidism treatment before the consultation. Patients' thyroid and liver function test indicators at the time of treatment were analyzed to determine the main cause of liver injury. The characteristics of liver injury were analyzed in the treatment group. Patients with severe thyroid toxicity and hyperthyroidism combined with liver injury were followed-up with anti-hyperthyroid therapy, mainly low-dose methimazole (MMI) and radioactive iodine therapy to evaluate its efficacy and safety. The comparison between data groups was performed by t-test, rank sum test and χ( 2) test. Results: Among the 43 cases with hyperthyroidism combined with liver injury, 19 were males and 24 were females, aged 49.0 ± 14.6 years-old; 16 cases (16/43, 37.21%) aged 40 to≤60 years- old, and 15 cases (15/43, 34.88%) aged > 60 years-old. There were 22 untreated cases (untreated group, accounting for 51.16%), and 21 treated cases with anti-hyperthyroidism (treatment group, accounting for 48.84%) at the time of consultation. Thyroid function indicators (FT3, FT4, TSH) and liver function indicators (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltransferase, total bilirubin) of the two groups were compared, and the difference was not statistically significant (P > 0.05). The order of liver injury from mild to severe in patients with different treatment options were: methimazole (MMI) < propylthiouracil < radioactive iodine <traditional Chinese herbal medicine. Low-dose MMI was safe and effective in patients with different degrees of liver injury with anti-hyperthyroidism treatment. Conclusion: The incidence of hyperthyroidism combined with liver injury is age-related, mainly due to thyroid toxicity. Low-dose MMI is safe and effective in patients with different degrees of liver injury with anti-hyperthyroidism treatment.

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Extensive infiltration of M2 macrophages plays a crucial role in repairing acute liver failure (ALF), however, the molecular pathways whereby mesenchymal stem cells (MSCs) induce M2 macrophage polarization remains unknown. We investigated the molecular pathways involved in MSC-induced M2 polarization and describe the potential therapeutic effects of M2 macrophages on ALF. The expression of M2 macrophage markers was significantly increased after M0 macrophages were co-cultured with MSCs in vitro. MSCs induced M2 macrophage polarization by activating STAT6, whereas a STAT6 inhibitor significantly inhibited the expression of M2 macrophage polarization markers (IL-4, CD163, TGF-β, IL-10 and Arg-1). Finally, M2 macrophages significantly reduced the secretion of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from injured hepatocytes. These results demonstrated that MSCs induced M2 macrophage polarization by activating STAT6, and that M2 macrophages increased the expression of anti-inflammatory factors to alleviate ALF.

BACKGROUND:The aim of this study was to determine the disease spectrum and drug types causing drug-induced liver injury (DILI) in northeast China, so that the affected population can be reminded of the need to increase their post-medication monitoring. METHODS:A total of 470 DILI patients hospitalized at Shengjing Hospital between 2013 and 2016 were involved in this retrospective study. RESULTS:There were significant differences in the disease spectrum of the different age groups (P < 0.001) and genders (P = 0.009). Drugs used to treat osteopathies, dermatitis and infections, as well as health care supplements, each accounted for > 10% of all drugs that caused DILI. The percentage of DILIs related to Chinese herbal medicines (CHMs) gradually increased with patient age (P = 0.002). The percentage of males taking health supplements or CHMs was significantly lower compared with females. Total bilirubin (β = 0.01, OR = 1.01, P < 0.001) and INR (β = 0.74, OR = 2.11, P < 0.001) were found to be independent predictors of liver damage. CONCLUSIONS:The main type of drug that causes DILI in northeast China is a CHM. There are differences in the disease spectrum found in DILI patients of different ages and gender. Making appropriate changes in the drug-taking habits of high-risk groups and the drugs used to treat high-risk underlying diseases, as well as increasing patient monitoring, may help to reduce the incidence of DILIs.