Pharmaceutical therapy for NASH is associated with lipid modulation, but the consensus on drug treatment is limited and lacks comparative analysis of effectiveness. A network meta-analysis was conducted to compare NASH drug classes in lipid modulation.

Online databases were searched for randomized controlled trails (RCTs) evaluating NASH treatments in biopsy-proven NASH patients. Treatments were classified into four groups: (1) inflammation, (2) energy, (3) bile acids, and (4) fibrosis based on the mechanism of action. A Bayesian network analysis was conducted with outcome measured by mean difference (MD) with credible intervals (Crl) and surface under the cumulative ranking curve (SUCRA).

Forty-four RCTs were included in the analysis. Bile acid modulating treatments (MD: 0.05, Crl: 0.03–0.07) were the best treatment for improvement in high-density lipid (HDL) cholesterol, followed by treatments modulating energy (MD: 0.03, Crl: 0.02–0.04) and fibrosis (MD: 0.01, Crl: −0.12 to 0.14) compared with placebo. The top three treatments for reduction in triglycerides were treatments modulating energy (MD: −0.46, Crl: −0.49 to −0.43), bile acids (MD: −0.22, Crl: −0.35 to −0.09), and inflammation (MD: −0.08, Crl: −0.13 to −0.03) compared with placebo. SUCRA found treatment modulating fibrosis (MD: −1.27, Crl: −1.76 to −0.79) was the best treatment for reduction in low-density lipid (LDL) cholesterol followed by treatment modulating inflammation (MD: −1.03, Crl: −1.09 to −0.97) and energy (MD: −0.37, Crl: −0.39 to −0.34) compared with placebo, but LDL cholesterol was worsened by treatments modulating bile acids.

Network analysis comparing the class effects of dyslipidemia modulation in NASH found that treatment targets can include optimization of atherogenic dyslipidemia. Future studies are required to evaluate the cardiovascular outcomes.

Non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus type 2 commonly coexist as a manifestation of metabolic syndrome. The presence of diabetes promotes the progression of simple fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis, and the presence of NAFLD increases the risk of diabetic complications. This coexistence affects a large part of the population, imposing a great burden on health care systems worldwide. Apart from diet modification and exercise, recent advances in the pharmacotherapy of diabetes offer new prospects regarding liver steatosis and steatohepatitis improvement, enriching the existing algorithm and supporting a multifaceted approach to diabetic patients with fatty liver disease. These agents mainly include members of the families of glucagon-like peptide-1 analogues and the sodium-glucose co-transporter-2 inhibitors. In addition, agents acting on more than one receptor simultaneously are presently under study, in an attempt to further enhance our available options.

Stem cell transplantation is a potential treatment option for liver cirrhosis (LC). Accurately and noninvasively monitoring the distribution, migration, and prognosis of transplanted stem cells using imaging methods is important for in-depth study of the treatment mechanisms. Our study aimed to develop Au-Fe3O4 silica nanoparticles (NPs) as tracking nanoplatforms for dual-modal stem cell imaging.

Au-Fe3O4 silica NPs were synthesized by seed-mediated growth method and co-precipitation. The efficiency and cytotoxicity of the NPs-labeled bone marrow-derived mesenchymal stem cells (BM-MSCs) were evaluated by Cell Counting Kit-8 assays, ICP-MS, phenotypic characterization, and histological staining. The biodistribution of labeled BM-MSCs injected through different routes (the hepatic artery or tail vein) into rats with LC was detected by magnetic resonance imaging (MRI), photoacoustic imaging (PAI), and Prussian blue staining.

Synthesized Au-Fe3O4 silica NPs consisted of a core (star-shaped Au NPs) and an outside silica layer doped with Fe3O4 NPs. After 24 h coincubation with 2.0 OD concentration of NPs, the viability of BM-MSCs was 77.91%±5.86% and the uptake of Au and Fe were (22.65±1.82) µg/mL and (234.03±11.47) µg/mL, respectively. The surface markers of labeled BM-MSCs unchanged significantly. Labeled BM-MSCs have osteogenic and adipogenic differentiation potential. Post injection in vivo, rat livers were hypointense on MRI and hyperintense on PAI. Prussian blue staining showed that more labeled BM-MSCs accumulated in the liver of the hepatic artery group. The severity of LC of the rats in the hepatic artery group was significantly alleviated.

Au-Fe3O4 silica NPs were suitable MRI/PAI dual-modal imaging nanoplatforms for stem cell tracking in regenerative medicine. Transhepatic arterial infusion of BM-MSCs was the optimal route for the treatment of LC.

Collagen β(1-O) galactosyltransferase 25 domain 1 (GLT25D1) is associated with collagen production and glycosylation, and its knockout in mice results in embryonic death. However, its role in liver fibrosis remains elusive, particularly in hepatic stellate cells (HSCs), the primary collagen-producing cells associated with liver fibrogenesis. Herein, we aimed to elucidate the role of GLT25D1 in HSCs.

Bile duct ligation (BDL)-induced mouse liver fibrosis models, primary mouse HSCs (mHSCs), and transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 human hepatic stellate cells were used in in vivo and in vitro studies. Stable LX-2 cell lines with either GLT25D1 overexpression or knockdown were established using lentiviral transfection. RNA-seq was performed to investigate the genomic differences. HPLC-MS/MS were used to identify glycosylation sites. Scanning electronic microscopy (SEM) and second-harmonic generation/two-photon excited fluorescence (SHG/TPEF) were used to image collagen fibril morphology.

GLT25D1 expression was upregulated in nonparenchymal cells in human cirrhotic liver tissues. Meanwhile, its knockdown attenuated collagen deposition in BDL-induced mouse liver fibrosis and inhibited mHSC activation. GLT25D1 was overexpressed in activated versus quiescence LX-2 cells and regulated in vitro LX-2 cell activation, including proliferation, contraction, and migration. GLT25D1 also significantly increased liver fibrogenic gene and protein expression. GLT25D1 upregulation promoted HSC activation and enhanced collagen expression through the TGF-β1/SMAD signaling pathway. Mass spectrometry showed that GLT25D1 regulated the glycosylation of collagen in HSCs, affecting the diameter of collagen fibers.

Collectively, the upregulation of GLT25D1 in HSCs promoted the progression of liver fibrosis by affecting HSCs activation and collagen stability.

The intricate relationship between metabolic-associated fatty liver disease (MAFLD) and maternal complications has rapidly become a significant health threat in pregnant women. The presence of MAFLD in pregnancy increases the maternal risk of metabolic complications and comorbidities for both mother and baby. The preexistence or development of MAFLD in pregnancy is a complex multifactorial disorder that can lead to further complications for mother and baby. Therefore, as pregnant women are severely underrepresented in clinical research, there is a great need for a fair inclusion of this group in clinical trials. This review aims to explore the effects of MAFLD during pregnancy in the context of maternal complications and outcomes and explore the effects of pregnancy on the development and progression of MAFLD within the context of maternal obesity, altered metabolic profiles, gestational diabetes and altered hormonal profiles. We also addressed potential implications for the presence of MAFLD during pregnancy and its management in the clinical setting.

Hepatocellular carcinoma (HCC) is rarely associated with autoimmune paraneoplastic syndromes. We report a case of anti-transcriptional intermediary factor-1 gamma (TIF1-γ)-positive dermatomyositis (DM) as clinical presentation of HCC recurrence in a 72-year-old male patient admitted to our hospital due to fatigue, myalgia, and typical skin rash. His medical history was notable for hepatitis C-related cirrhosis, successful treatment with direct-acting antiviral agents, and previously efficacious treatment of HCC. Laboratory testing showed significant rhabdomyolysis with anti-TIF1-γ antibodies at high titer, and DM was diagnosed. After a careful diagnostic workup, HCC recurrence was diagnosed. After first-line corticosteroid treatment, azathioprine and intravenous immunoglobulin treatments were administered; unfortunately, he mounted only partial response. Owing to the compromised performance status, no HCC treatment was feasible, and, according to international guidelines, he received only best supportive care. Here, we discuss the diagnostic, prognostic, and pathogenic roles of anti-TIF1-γ antibodies associated with paraneoplastic DM and the scant literature data on its occurrence in HCC patients. Considering the TIF1 gene family’s established role in oncogenesis, we also review the role of TIF1-γ as a tumor-related neoantigen, leading to the development of clinically overt anti-TIF1-γ antibodies-positive DM.

The study aimed to create a new staging model for radiotherapy-based treatment for prognostic hepatocellular carcinoma (HCC) classification.

The training cohort comprised 658 patients receiving stereotactic body radiotherapy and external validation cohort comprised 533 patients receiving three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. We established a modified staging system as follows: stage I, solitary nodule without macrovascular invasion, or 2–3 nodules no more than 3.0 cm apart, and performance status (PS) 0–2 (Ia: ALBI-1 grade; Ib: ALBI-2 or 3 grade); stage II: 2–3 nodules with any one nodule more than 3.0-cm apart, or ≥4 nodules, and performance status 0–2 (IIa: ALBI-1 grade; IIb: ALBI-2 grade); stage III: macrovascular invasion, regional lymph node metastasis or distant metastasis, and performance status 0–2 (IIIa: ALBI-1 grade; IIIb: ALBI-2 grade); stage IV: performance status 3–4, or performance status 0–2 with ALBI-3 grade. We analyzed long-term overall survival based on different stages.

The staging model showed an excellent ability to discriminate patients according to four stages and seven substages with notably different curves in the training and validation cohort. The median survival decreased from stages I to IV with 63.0 months in stage I (not reached in Ia, and 53.0 months in Ib), 24.0 months in stage II (28.0 months in IIa, and 22.0 months in IIb), 11.0 months in stage III (18.0 months in IIIa, and 9.0 months in IIIb), and less than 9.0 months in stage IV in the training cohort.

The modified staging model may provide an alternative for clinical radiation oncologists.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is prevalent in patients with chronic hepatitis B (CHB). The effect of the histologic MAFLD phenotype on long-term CHB outcomes is unknown. We performed a longitudinal study to determine the prognostic relevance of biopsy-proven hepatic steatosis and steatohepatitis for CHB patients.

Clinical and laboratory data were obtained from CHB patients who underwent liver biopsy during 2002–2008 and were treated with antiviral drugs. A hepatopathologist reviewed the biopsy specimens. Cox proportional hazards regression was used to estimate the adjusted hazard ratio (aHR) of outcomes, including all-cause mortality, liver transplantation, and liver-related events.

In accordance with Brunt’s classification, 408 patients had steatohepatitis (n=34), “steatosis but not steatohepatitis” (n=118), or “non-steatosis” (n=256). All steatohepatitis patients had features of metabolic dysfunction. Over a mean follow-up of 13.8±3.1 years, 18 patients died or underwent liver transplantation. In multivariate-adjusted analysis, steatohepatitis (aHR, 6.37; 95% confidence interval [CI]: 1.59–25.5) compared with non-steatosis and advanced fibrosis (aHR, 11.3; 95% CI: 1.32–96.3) compared with no fibrosis were associated with overall mortality/liver transplantation. Thirty-five patients developed 43 liver-related events, among which 32 were hepatocellular carcinoma. These events were associated with steatohepatitis (aHR, 5.55; 95% CI: 2.01–15.3) compared with non-steatosis and advanced fibrosis (aHR, 6.23; 95% CI: 1.75–22.2) compared with no fibrosis. The steatosis but not steatohepatitis group had a non-significantly higher risk of overall mortality and liver-related events.

Metabolic dysfunction-associated steatohepatitis increased the risk of long-term mortality/transplantation and liver-related events in CHB patients.

Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are the two predominant urologic diseases affecting aging men. As a matter of fact, 95–98% of elderly men with prostate as their “primary organ disease” for consulting urologists have either the clinical diagnosis of BPH, PCa or both. Other primary diagnoses of the prostate such as sarcoma, lymphoma or isolated bacterial prostatitis (not in the context of a systemic urinary tract infection) are rare entities. Although BPH and PCa are very common, their interaction is currently not well understood. Numerous clinical studies and meta-analysis reviews have demonstrated a negative correlation between prostate BPH size and the probability of PCa presence, but little is known to explain this clinical phenomenon. Recent histo-anatomical and magnetic resonance imaging studies have revealed data leading to a hypothesis indicating the expanding transition zone (TZ) in a growing BPH prostate causes mechanical stress within the peripheral zone (PZ) with secondary fibrosis and atrophy of the glands within the PZ. This dynamic interaction of the TZ against the PZ in a growing BPH-prostate could explain the negative correlation between BPH size and PCa incidence. The purpose of this review is to present and discuss the evolving hypothesis that prostate size may matter and be protective against prostate cancer.

Cadmium (Cd) is toxic to blood cells and other tissues of the body. This study examined the influence of Hibiscus sabdarrifa anthocyanins (HSA) pretreatment on selected blood parameters in rats administered Cd.

Forty Wistar rats were randomized into eight groups with five rats in each group. The rats were handled in two experimental periods: a five-day acute study and 15-day chronic toxicity study. The experimental groups were the control, Cd, HSA and HSA+Cd groups.

Compared with the healthy control, Cd administration significantly increased the counts of white blood cells (WBC), but decreased red blood cells (RBC), platelets, packed cell volume (PCV), hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular hemoglobin (MCH) in rats (p < 0.05 for all). In contrast, treatment with HSA significantly reduced the hematological toxicity of Cd in rats by decreasing the counts of WBC, but increasing RBC, PCV, Platelets, Hb, MCV, MCHC, and MCH values in rats.

The results indicate that HSA treatment ameliorates the Cd-caused hematological toxicity in rats and may be valuable for intervention of Cd poisoning.

Anti-tuberculosis (anti-TB) drug-induced liver injury (AT-DILI) is the most common side effect in patients who received anti-TB therapy. AT-DILI management includes monitoring liver function until symptoms arise in patients without high-risk factors for liver damage. The present study aimed to investigate the effect of liver function test (LFT) abnormal identification on the risk of DILI, including liver failure and anti-TB drug resistance in patients without high-risk factors.

A total of 399 patients without high-risk factors for liver damage at baseline and who experienced LFT abnormal during the 6 months of first-line anti-TB treatment were enrolled. The Roussel Uclaf Causal Relationship Assessment Method (RUCAM, 2016) was applied in suspected DILI. The correlations between the time of LFT abnormal identification and DILI, liver failure, and anti-TB drug resistance were analyzed by smooth curve fitting and multivariable logistic regression models.

Among all study patients, 131 met the criteria for DILI with a mean RUCAM causality score of 8.86±0.63. 26/131 and 105/131 were in the probable grading and highly probable grading, respectively. The time of abnormal LFT identification was an independent predictor of DILI, liver failure, and anti-TB drug resistance in the crude model and after adjusting for other risk patient factors. The time of abnormal LFT identification was positively correlated with DILI, liver failure, and anti-TB drug resistance. The late identification group (>8 weeks) had the highest risk of DILI, followed by liver failure compared with the other two groups.

The time to identification of LFT was positively correlated with DILI, liver failure, and anti-TB drug resistance. The risk of DILI and liver failure was significantly increased in the late identification group with abnormal LFT identified after 8 weeks compared with 4 and 8 weeks. Early monitoring of LFT is recommended for patients without the high-risk factor of DILI after anti-TB treatment is initiated.

The rising global prevalence of metabolic diseases has increased the prevalence of non-alcoholic fatty liver disease (NAFLD), leading to an increase in cases of NAFLD-related hepatocellular carcinoma (HCC). To provide an updated literature review detailing epidemiology, risk factors, pathogenic pathways, and treatment strategies linked to NAFLD-related HCC, we conducted a literature search on PubMed from its inception to December 31, 2021. About 25% of the global population suffers from NAFLD. The annual incidence of HCC among NAFLD patients is approximately 1.8 per 1,000 person-years. Older age, male sex, metabolic comorbidities, unhealthy lifestyle habits (such as smoking and alcohol consumption), physical inactivity, genetic susceptibility, liver fibrosis, and degree of cirrhosis in NAFLD patients are important risk factors for NAFLD-related HCC. Therefore, low-calorie diet, moderate-intensity exercise, treatment of metabolic comorbidities, and cessation of smoking and alcohol are the main measures to prevent NAFLD-related HCC. In addition, all patients with advanced NAFLD-related fibrosis or cirrhosis should be screened for HCC. Immune suppression disorders and changes in the liver microenvironment may be the main pathogenesis of NAFLD-related HCC. Hepatic resection, liver transplantation, ablation, transarterial chemoembolization, radiotherapy, targeted drugs, and immune checkpoint inhibitors are used to treat NAFLD-related HCC. Lenvatinib treatment may lead to better overall survival, while immune checkpoint inhibitors may lead to worse overall survival. Given the specific risk factors for NAFLD-related HCC, primary prevention is key. Moreover, the same treatment may differ substantially in efficacy against NAFLD-related HCC than against HCC of other etiologies.

Patients with biliary atresia (BA) are prone to hepatic decompensation, which might eventually lead to death. This study aimed to identify the possible risk factors affecting in-hospital death in BA patients in China.

We collected data from the Hospital Quality Monitoring System, a national inpatient database. All patients aged up to 2 years old with a diagnosis of BA were included. The subjects were divided to three groups, including Kasai portoenterostomy (KP), liver transplantation (LT), and no surgery. Logistic regression with Firth’s method was performed to identify potential influencing variables associated with in-hospital death.

During the year 2013 to 2017, there were 14,038 pediatric admissions with a diagnosis of BA. The proportion of in-hospital death in pediatric BA admissions was 1.08%. Compared with patients under six months, there was a higher risk of in-hospital death for children aged six months to 1 year and 1–2 years old. Clinical signs, including cirrhosis, variceal bleeding, and hepatic encephalopathy, were significantly associated with the risk of in-hospital death. In no surgery group, compared to those in Beijing and Shanghai, BA patients admitted in other districts had a lower risk of in-hospital death (OR=0.39, 95% CI: 0.21, 0.70). However, in the LT group, patients admitted in other districts had a higher risk of in-hospital death (OR=9.13, 95% CI: 3.99, 20.87).

In-hospital survival remains unsatisfactory for pediatric BA patients with severe complications. Furthermore, more resources and training for BA treatment, especially LT, are essential for districts with poor medical care in the future.

Alcoholic liver disease is one of the most common chronic liver diseases in the world. It is a liver disease caused by prolonged heavy drinking and its main clinical features are nausea, vomiting, enlargement of the liver, and jaundice. Recent studies suggest that Kupffer cell-mediated inflammatory response is a core driver in the development of alcoholic steatohepatitis and alcoholic liver fibrosis. As a danger signal, extracellular ATP activates the assembly of NLPR3 inflammasome by acting on purine P2X7 receptor, the activated NLRP3 inflammasome prompts ASC to cleave pro-cCaspase-1 into active caspase-1in KCs. Active caspase-1 promotes the conversion of pro-IL-1β to IL-1β, which further enhances the inflammatory response. Here, we briefly review the role of the P2X7R-NLRP3 inflammasome axis in the pathogenesis of alcoholic liver disease and the evolution of alcoholic steatohepatitis and alcoholic liver fibrosis. Regulation of the inflammasome axis of P2X7R-NLRP3 may be a new approach for the treatment of alcoholic liver disease.

The surfaces of the human body, including those of internal organs, are colonized by diverse commensal microbes. As we expand our understanding of these microbes, these micro-organisms increasingly seem to play important roles in human disease development. The most abundant and functional among these communities is the gut microbes. They not only influence food digestion in native intestinal habitats but also play an essential role in the neurological system. The communication between the gut microbiota and the brain has been partially revealed by new discoveries in the past few years, which has strengthened our knowledge of how the gut microbiota modulates neurological diseases such as ischemic stroke. Ischemic stroke is characterized by poor outcomes, including high disability and fatality rates. Recent investigations among clinical trials and animal experiments have provided some intriguing hints regarding the role of gut microbiota in ischemic stroke outcomes, and a few experimental therapeutic approaches based on gut microbiota have shown promising results. In this review, we discuss the current findings and theories regarding the interaction between gut microbiota and ischemic stroke, and highlight the potential role of gut microbiota in treating ischemic stroke.

The impact of nonalcoholic fatty liver disease (NAFLD) on the treatment outcome of chronic hepatitis B (CHB) is undefined and deserves an in-depth investigation.

Histologically-proven CHB receiving first-line antiviral regimens as initial therapy was enrolled and grouped by the concurrence of NAFLD, and followed up at six monthly intervals. Therapeutic response related data were recorded and compared at multiple time points. Kaplan-Meier and Cox regression analyses were utilized to estimate the impact of NAFLD on complete virological response (CVR).

We enrolled 267 patients (CHB: 164; CHB with NAFLD: 103) with comparable follow-up durations. They were also comparable in baseline HBV DNA levels and HBeAg positivity. Patients with concomitant NAFLD showed less significant decline in HBV DNA, qHBsAg, pgRNA, and liver enzyme levels over time; moreover, their cumulative incidences of CVR were significantly lower and that of low-level viremia (LLV) were significantly higher at 6, 12, 18, 24 months. First CVR of CHB was delayed with the presence NAFLD (11.0 vs. 7.0 months, p<0.001) and further prolonged with higher grade of liver steatosis (Grade 2–3 vs. 1: 13.0 vs. 9.0 months). On multivariate analysis, HBeAg positivity (HR: 0.650, p=0.036), grade of steatosis (G2 [HR: 0.447, p=0.004]; G3 [HR: 0.085, p=0.002]) and HBV DNA (log10 IU/mL) (HR: 0.687, p<0.001) were significantly associated with delayed CVR, whereas grade of necroinflammation (HR: 1. 758, p<0.001) accelerated the CVR.

In CHB patients receiving initial antiviral therapy, NAFLD was associated with higher levels of HBV DNA, pgRNA, and liver enzymes, and higher incidence of LLV and delayed CVR.

The study established and compared the efficacy of the clinicoradiological model, radiomics model and clinicoradiological-radiomics hybrid model in predicting the microvascular invasion (MVI) of hepatocellular carcinoma (HCC) using gadolinium ethoxybenzyl diethylene triaminepentaacetic acid (Gd-EOB-DTPA) enhanced MRI.

This was a study that enrolled 602 HCC patients from two institutions. Least absolute shrinkage and selection operator (Lasso) method was used to screen for the most important clinicoradiological and radiomics features that predict MVI pre-operatively. Three machine learning algorithms were used to establish the clinicoradiological, radiomics, and clinicoradiological-radiomics hybrid models. Area under the curve (AUC) of receiver operating characteristic (ROC) curves and Delong’s test were used to compare and quantify the predictive performance of the models.

The AUCs of the clinicoradiological model in training and validation cohorts were 0.793 and 0.701, respectively. The radiomics signature of arterial phase (AP) images alone achieved satisfying predictive efficacy for MVI, with AUCs of 0.671 and 0.643 in training and validation cohort, respectively. The combination of clinicoradiological factors and fusion radiomics signature of AP and VP images achieved AUCs of 0.824 and 0.801 in training and validation cohorts, 0.812 and 0.805 in prospective validation and external validation cohorts, respectively. The hybrid model provided the best prediction results. The results of the Delong test revealed that there were statistically significant differences among the clinicoradiological-radiomics hybrid model, clinicoradiological model, and radiomics model (p<0.05).

The combination of clinicoradiological factors and fusion radiomics signature of AP and VP images based on Gd-EOB-DTPA-enhanced MRI can effectively predict MVI.

Urachal carcinoma (UC) cases are rare but aggressive that pose significant diagnostic and therapeutic challenges. To summarize the diagnostic features of UC, we report our case findings.

Retrospectively analyzed the clinical features of patients with UC between 2010 and 2020 at our center. Patient demographics, clinical history, treatment, and follow-up information were obtained.

All 11 UC patients with a mean age of 54.2 years, including 8 men and 3 women. The initial symptom in 7 cases was painless gross hematuria, followed by urinary tract irritation and abdominal pain. Pathological findings revealed malignancies in all patients, including three mucinous UC, six moderate differentiated UC, one poorly differentiated UC, and one undifferentiated typed UC. Most of the patients underwent extended partial cystectomy. In addition, the majority of patients (82%) had a short duration of follow-up (2–36 months), and 18% of patients were lost to follow-up. As a result, the average postoperative follow-up time was 19.7 months and the 2-year survival rate was 54.5%.

The incidence of UC is concealed and patients often complain about hematuria and mucinuria. There is a lack of effective systemic treatment, and the prognosis of UC is poor.