Liver International最新文献

Introduction: Racial/ethnic disparities have been previously reported in renal and hepatic disease care; however, acute kidney injury (AKI) in the setting of cirrhosis (hepatorenal syndrome [HRS]-AKI) despite its complexity requiring a multidisciplinary approach, remains understudied.

Methods: To identify unique associations of clinical and sociodemographic factors with mortality and length of stay (LOS) among patients hospitalised with HRS-AKI, hierarchical regression analysis was conducted, along with a mediation analysis to estimate how race-related differences in in-hospital mortality were influenced by payer type, area household income, and clinical severity.

Results: Black patients demonstrated a significantly higher odds of in-hospital mortality, compared to their white counterparts, adjusting for (1) sex and age, (2) sex, age, payer type, and area household income and (3) sex, age, and clinical severity [OR 1.16-1.20, 95% confidence intervals (CI) > 1]. Higher mortality rates among Black patients were partially mediated by clinical severity and area household income [proportion mediated (PM): _0.1890.19_0.192 and _0.160.17_0.18, respectively]. Black patients with HRS-AKI had longer LOS than White patients. Hispanic patients tended to have lower odds of in-hospital mortality [OR: _0.770.86_0.97] despite their lower income and more severe illness.

Conclusion: Our nationwide US study demonstrated that, partly due to higher clinical severity and lower household income, Black patients with HRS-AKI experience higher inpatient mortality, compared to White patients. On the other hand, Hispanics with HRS-AKI have a survival advantage. More awareness is warranted to address racial disparities in HRS-AKI outcomes.

Background and aims: This study aims to develop and validate a machine learning (ML) model predicting hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients after the first 5 years of entecavir (ETV) or tenofovir (TFV) therapy.

Methods: CHB patients treated with ETV/TFV for > 5 years and not diagnosed with HCC during the first 5 years of therapy were selected from two hospitals. We used 36 variables, including baseline characteristics (age, sex, cirrhosis, and type of antiviral agent) and laboratory values (at baseline, at 5 years, and changes between 5 years) for model development. Five machine learning algorithms were applied to the training dataset and internally validated using a test dataset. External validation was performed.

Results: In years 5-15, a total of 279/5908 (4.7%) and 25/562 (4.5%) patients developed HCC in the derivation and external validation cohorts, respectively. In the training dataset (n = 4726), logistic regression showed the highest area under the receiver operating curve (AUC) of 0.803 and a balanced accuracy of 0.735, outperforming other ML algorithms. An ensemble model combining logistic regression and random forest performed best (AUC, 0.811 and balanced accuracy, 0.754). The results from the test dataset (n = 1182) verified the good performance of the ensemble model (AUC, 0.784 and balanced accuracy, 0.712). External validation confirmed the predictive accuracy of our ensemble model (AUC, 0.862 and balanced accuracy, 0.771). A web-based calculator was developed (http://ai-wm.khu.ac.kr/HCC/).

Conclusions: The proposed ML model excellently predicted HCC risk beyond year 5 of ETV/TFV therapy and, therefore, could facilitate individualised HCC surveillance based on risk stratification.

Background and aims: The safety and tolerability of bulevirtide (BLV), a novel entry inhibitor of hepatitis delta virus, were evaluated in an integrated analysis of clinical trial results from patients with chronic hepatitis delta (CHD).

Methods: Week 48 on-treatment clinical and laboratory results from two Phase 2 trials (MYR203 [NCT02888106] and MYR204 [NCT03852433]) and one Phase 3 trial (MYR301 [NCT03852719]) were pooled (N = 269). Patients were grouped as follows: BLV 2 mg (n = 64), BLV 10 mg (n = 115), pegylated interferon-alfa (n = 39) and control (n = 51). The control group consisted of patients assigned to the delayed treatment group in Study MYR301.

Results: Adverse events (AEs) that occurred more frequently with BLV 2 mg and BLV 10 mg versus control included increased total bile acid levels (20% and 17% vs. 0%), injection-site reactions (16% and 20% vs. 0%), headache (16% and 17% vs. 0%), pruritus (11% and 10% vs. 0%) and eosinophilia (9% and 4% vs. 0%). Increases in total bile acid levels were observed with BLV without clear correlation with AEs, such as pruritus, eosinophilia or vitamin D deficiency. Grade 3 or 4 study drug-related AEs occurred in a higher proportion of patients receiving pegylated interferon-alfa (51%) than with BLV 2 or 10 mg (3% and 4%, respectively). There were no serious AEs related to BLV, and no patients discontinued BLV due to an AE. Neither hepatic decompensation nor death occurred.

Conclusions: BLV monotherapy was safe and well tolerated through 48 weeks of treatment in patients with CHD.

Trial registration: NCT02888106, NCT03852433 and NCT03852719.

Background: M2 macrophage-derived exosomes have been identified to modulate hepatocellular carcinoma (HCC) progression. E-twenty-six (ETS) variant transcription factor 4 (ETV4) shows protumoral effects in HCC. Here, we aimed to probe whether ETV4 performed oncogenic effects on HCC by macrophage-derived exosomes and its associated mechanism.

Methods: Exosomes were isolated from macrophages and co-cultured with HCC cells. qRT-PCR and western blotting were utilised for the detection of mRNA and protein. Cell survival was evaluated using EdU assay and flow cytometry. Glycolysis was determined by measuring the glucose uptake, lactate production, and ATP levels. Cell stemness was assessed by sphere formation and flow cytometry. The interaction between ETV4 and SULT2B1 (sulfotransferase family 2B member 1) was determined by a dual-luciferase reporter and chromatin immunoprecipitation assays. In vivo assay was performed by establishing mouse xenograft models.

Results: ETV4 was highly expressed in the exosomes of M2 macrophages and could be internalised by HCC cells. ETV4 derived from M2 macrophage exosomes promoted HCC cell proliferation, glycolysis and stemness in vitro, and enhanced HCC growth in nude mice. Mechanistically, ETV4 interacted with SULT2B1 and promoted it transcription. SULT2B1 silencing suppressed HCC cell proliferation, glycolysis and stemness. In addition, exosomal ETV4 derived from M2 macrophage performed its effects by modulating SULT2B1.

Conclusion: ETV4 derived from M2 macrophage exosomes promoted HCC cell proliferation, glycolysis and stemness by interacting with SULT2B1, suggesting a novel insight into developing exosome-based therapy for HCC.

Background: Secondary sclerosing cholangitis (SSC), is one of the phenotypes of DILI first described in the 1980s. Check point inhibitors (CPIs) are currently the most frequent cause of SCC.

Aims: To describe the epidemiology, clinical and biochemical features at presentation, differential diagnoses, pathophysiology, imaging, histological characteristics and management associated with SSC.

Materials and methods: A language and date-unrestricted Medline literature search was conducted to identify case reports and clinical series on SSC with special emphasis on CPIs (2007-2023).

Results: We identified 19 different drugs that have been shown to induce SSC. A total of 64 cases with SSC due to CPIs are presented. This was mostly seen in patients treated with anti-Programmed cell death (PD)-1/PD-L1 inhibitors. The most frequent presenting signs and symptoms were abdominal pain and jaundice. Large-duct cholangitis induced by CPIs is a very rare condition while small-duct cholangitis is more common. Nivolumab and pembrolizumab were the most commonly implicated agents. Biopsies have revealed predominant CD8+ T cell infiltration in biliary strictures. Corticosteroids is linked to a low frequency of success and is the only agent recommended to begin the treatment.

Conclusions: CPIs-induced SSC seems to affect the entire biliary system. Clinicians should consider and suspect SSC when a probable CPIs-induced hepatitis does not respond to corticosteroids. Additionally, further randomized, controlled trials should prospectively investigate alternative therapies for treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by metabolic triggers and genetic predisposition. Among the genetic MASLD risk variants identified today, the common PNPLA3 148M variant exerts the largest effect size of MASLD heritability. The PNPLA3 148M protein is causatively linked to the development of liver steatosis, inflammation and fibrosis in experimental studies and is therefore an appealing target for therapeutic approaches to treat this disease. Several PNPLA3 targeted approaches are currently being evaluated in clinical trials for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), the most severe form of MASLD and promising proof of principle data with reduced liver fat content in homozygous PNPLA3 148M risk allele carriers has been reported from phase 1 trials following hepatic silencing of PNPLA3. Thus, targeting PNPLA3, the strongest genetic determinant of MASH may hold promise as the first precision medicine for the treatment of this disease. A histological endpoint-based phase 2b study has been initiated and several more are expected to be initiated to evaluate treatment effects on histological MASH and liver fibrosis in participants being homozygous for the PNPLA3 148M risk allele variant. The scope of this mini-review is to briefly describe the PNPLA3 148M genetics, function and preclinical experimental evidence with therapeutic approaches targeting PNPLA3 as well as to summarise the PNPLA3 based therapies currently in clinical development.

Introduction: The safety of continuing anticoagulation therapy during endoscopic variceal ligation (EVL) remains controversial. We performed a systematic review and meta-analysis to evaluate the safety of anticoagulation therapy in EVL.

Methods: We systematically searched four electronic databases from their inception until 1 June 2024, for studies that evaluated anticoagulation use and risk of rebleeding among patients undergoing EVL. The primary endpoint was rebleeding after EVL. The secondary endpoints were post-banding ulcer bleeding (PBUB) and variceal eradication rate. The PROSPERO registration number is CRD42024556094.

Results: A total of 5617 participants from nine studies (eight cohort studies and one randomised trial) were included. The most common type of anticoagulation is low-molecular-weight heparin, followed by warfarin and direct oral anticoagulants (DOAC). The pooled risk of rebleeding was 10.9% (95%CI: 6.3-16.5; I² = 65.5%). Concurrent anticoagulation during EVL did not increase the risk of overall rebleeding (OR, 1.10; 95%CI: 0.85-1.42, I² = 0%), PBUB (OR, 1.04; 95%CI, 0.48-2.24; I² = 24%) or severe bleeding (OR, 0.94; 95%CI, 0.31-2.85; I² = 0%). Variceal eradication rates were similar, regardless of the use of anticoagulation therapy during EVL.

Conclusion: Anticoagulation did not increase the risk of rebleeding in patients who underwent EVL. Since the certainty of evidence is low, these findings should be confirmed in future randomised trials.