Liver cancer international最新文献

Alpha-1 antitrypsin deficiency (A1ATD) is an inherited metabolic disorder caused by a mutation (ZZ) in the SERPINA1 gene. Carriers are predisposed to liver and lung pathology. The severity of A1ATD-associated liver disease is highly variable, necessitating further characterisation. This study aims to investigate the risk and extent of liver disease and the prevalence of liver transplantation in ZZ A1ATD patients. Several established databases, including Ovid, EBSCO, PubMed, and Cochrane Library, were searched from inception to May 12, 2024. Data were pooled using a random effects model, and study weight was calculated using the inverse variance method. Crude odds ratios (cOR) were calculated using participants with the MM genotype as the comparator. The study was registered in PROSPERO (CRD42022335666). Of the 4420 studies identified, 45 studies and 8638 A1ATD patients (38.8% female) were included. ZZ A1ATD patients demonstrate an increased risk of liver diseases compared to controls, including steatosis (crude odds ratio (cOR): 1.52 [95% CI: 1.21, 1.91]), fibrosis (cOR: 9.85 [95% CI: 5.70, 17.03]), cirrhosis (cOR: 10.43 [95% CI: 5.51, 19.73]), and liver cancers (cOR: 14.12 [95% CI: 6.50, 30.66]). The prevalence of liver transplantation is considerable, with rates reaching 5% [95% CI: 0.00, 12.34]. Our findings confirm the substantial burden of liver disease in ZZ A1ATD patients, including subclinical manifestations such as steatosis and fibrosis that may remain undetected. Given the lack of approved treatments for A1ATD-associated liver disease, prioritising the development of novel therapies to stop or reverse liver disease is essential.

MSDC-0602 K is a second-generation insulin sensitizer that inhibits the mitochondrial pyruvate carrier without activating the transcription factor PPARγ. The EMMINENCE phase IIb trial evaluated MSDC-0602 K in patients with metabolic dysfunction-associated steatohepatitis (MASH). MSDC-0602 K missed statistical significance on endpoints based on liver histology while producing significant reductions in metabolic biomarkers. Here, we assessed the extracellular matrix-based biomarkers PRO-C3 and PRO-C6, surrogates of collagen type III synthesis and the profibrotic, pro-inflammatory fragment endotrophin. 392 MASH patients were randomised to placebo (PL), 62.5 mg, 125 mg or a 250 mg daily dose of MSDC-0602 K for 12 months. 334 completed the study. The primary efficacy endpoint was defined as an improvement of ≥ 2 points in NAS score, with ≥ 1 decrease in either ballooning or inflammation and no increase in fibrosis stage. Blood samples were collected at baseline, 6 months, and 12 months to assess biochemical markers PRO-C3 and PRO-C6. The 125 mg and 250 mg doses of MSDC-0602 K reduced PRO-C3 at 6 months (p = 0.0103 and p = 0.026 respectively) and 12 months (p = 0.0274 and p = 0.0311) compared to placebo. Furthermore, the 62.5 mg and 250 mg doses reduced PRO-C6 at 12mo (p = 0.0467 and p = 0.0266) compared to placebo. Treated patients who reached the primary endpoint had lower baseline PRO-C3 (p = 0.026), and PRO-C3 levels discriminated between regressing, stable or progressing fibrosis (p = 0.0076). MSDC-0602 K significantly reduced PRO-C3 and PRO-C6, suggesting anti-fibrotic and pro-metabolic effects. Lower baseline fibroblast activity (PRO-C3) at baseline was associated with improvement in fibrosis, while higher baseline PRO-C3 was associated with fibrosis progression. Our findings suggest that MSDC-0602 K has anti-fibrogenesis and pro-metabolic effects not detected by liver histology.

Trial Registration: EMMINENCE clinical trial number (ClinicalTrials.gov NCT02784444)

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. Therapeutic options are limited, and therefore new therapeutic targets are needed. Cathepsins, lysosomal proteases, are implicated in various types of cancer. While intracellular cathepsins have various physiological functions, their extracellular secretion can lead to pathological effects. Cathepsin B (CTSB) stays active at neutral pH and contributes to several liver pathologies, including HCC. However, the mechanisms by which extracellular CTSB contributes to HCC remain unclear. Hence, this study aimed to investigate the role of extracellular CTSB in HCC. Cell and spheroid viability of HepG2 and Huh-7 cells was assessed after treatment with extracellular and intracellular CTSB inhibitors. A chorioallantoic membrane HCC xenograft model was used to study the effect of combined extracellular CTSB inhibitor and chemotherapy treatment on tumour growth, apoptosis, proliferation and angiogenesis. The UK Biobank proteomics data was used to determine the potential role of CTSB in HCC patients. Inhibition of extracellular CTSB significantly decreased the viability of HepG2 and Huh-7 cells in both monolayers and spheroids compared to intracellular CTSB inhibition. The chorioallantoic membrane model demonstrated that extracellular CTSB inhibition decreased the ratio of proliferation-apoptosis and, in the presence of paclitaxel, tumour angiogenesis, which resulted in a smaller tumour mass. Furthermore, compared to healthy controls, HCC patients demonstrated higher plasma levels of CTSB which were associated with a higher mortality risk. In conclusion, targeting extracellular CTSB could be a promising therapeutic strategy for HCC, since it decreases angiogenesis and proliferation, while it increases apoptosis.

Chronic liver diseases frequently progress to liver fibrosis, characterized by the accumulation of extracellular matrix (ECM) proteins and the formation of fibrous scars. This fibrous tissue disrupts normal liver architecture, impairing its physiological functions. Advanced liver fibrosis can lead to cirrhosis, portal hypertension and liver failure, often necessitating transplantation. Hepatic stellate cells (HSCs) are pivotal in collagen production and play a crucial role in the fibrotic process. Notably, mild to moderate fibrosis can be reversed upon removal of its causative agents, with recovery rates varying based on the cause and severity of fibrosis. Emerging anti-fibrotic therapies focus on inhibiting fibrogenic cell accumulation and preventing ECM deposition. This review highlights herbal extracts with proven effects on HSCs in vivo, showing potential in mitigating liver fibrosis. These extracts inhibit HSC proliferation and ECM release by targeting critical signalling pathways, including TGF-β, NF-κB, MAPK, STAT3 and NRF2. While many of these plants have been validated in pre-clinical studies, further research is needed to identify active compounds and establish clinical efficacy.

It remains unclear whether alcohol intake and cardiometabolic factors are simultaneously associated with liver fibrosis progression in Japanese obese patients. This study investigated factors influencing liver fibrosis progression using the Aspartate Aminotransferase/Platelet Ratio Index (APRI), which does not include age. We conducted a cross-sectional study of 26 737 obese (BMI ≥ 25 kg/m²) adults undergoing health checkups. Steatotic liver disease (SLD) was diagnosed via ultrasonography. Clinical characteristics were analysed according to BMI category and APRI to identify risk factors for advanced liver fibrosis (APRI > 1.0). The prevalence of type 2 diabetes, hypertension, and SLD increased with increasing BMI. On multivariable analysis in male, significant risk factors for advanced liver fibrosis included increased BMI (BMI 30–34.9 kg/m²: OR 2.64, 95% CI 1.89–3.69, p < 0.001; BMI 35–39.9 kg/m²: OR 2.67, 95% CI 1.89–3.69, p = 0.002; BMI ≥ 40 kg/m²: OR 3.51, 95% CI 1.24–9.96, p = 0.018), SLD (OR 2.13, 95% CI 1.49–3.05, p < 0.001), moderate alcohol intake (OR 1.36, 95% CI 1.03–1.79, p = 0.031), heavy alcohol intake (OR 4.31, 95% CI 2.90–6.40, p < 0.001), high blood pressure (OR 1.30, 95% CI 1.01–1.67, p = 0.044), and high fasting blood glucose (OR 1.61, 95% CI 1.12–2.28, p = 0.008). In female, only age > 65 years (OR 3.02, 95% CI1.93–4.73, p < 0.001), BMI, and high uric acid (OR 2.06, 95% CI 1.15–3.68, p = 0.015) were extracted. In an obese male, alcohol intake and cardiometabolic factors were associated with liver fibrosis progression based on APRI, independent of elevated BMI and SLD.

Aspirin and NSAIDs may be beneficial in chronic liver diseases. We explored the effect of exposure to anti-inflammatory drugs in patients with chronic liver disease with regard to adverse liver events, cancers and mortality. A cohort of patients with chronic liver disease 2005–2020 (n = 21 439) was studied. All patients were hospitalised in Region Stockholm. Data from the Patient Register, Prescribed Drug Register, Death Certificate Register, Cancer Register, two laboratories and Stockholm Center for Health Data were combined. We analysed death, adverse liver events, liver cancers and all cancers in relation to drug exposure. During follow-up 10 279 patients (47.9%) died. There was a reduced risk for all cancers combined when patients were exposed to aspirin (aHR 0.68; 95% CI 0.63–0.73) and NSAIDs (aHR 0.80; 95% CI 0.75–0.86) and a reduced risk of liver cancer in patients exposed to aspirin (aHR 0.48; 95% CI 0.41–0.57) and to NSAIDs (aHR 0.71; 95% CI 0.62–0.82). There was a reduced overall mortality risk for patients exposed to NSAIDs (aHR 0.68; 95% CI 0.64–0.72) and a reduced mortality risk for patients exposed to aspirin (aHR 0.86; 95% CI 0.82–0.91) after adjusting for comorbidities and severity of the liver disease. Patients with alcohol-associated liver disease exposed to aspirin had reduced mortality risk (aHR 0.82; 95% CI 0.76–0.89) and exposure to NSAIDs also reduced the mortality risk (aHR 0.74; 95% CI 0.69–080). Exposure to aspirin or NSAIDs in patients with chronic liver diseases was associated with reduced cancer risks including risk for liver cancer and decreased overall mortality risk.

Carcinoid tumours are slow-growing neuroendocrine neoplasms mainly affecting the gastrointestinal tract, the respiratory tree, ovaries and kidneys. Approximately 20% of patients with carcinoid tumour are affected by carcinoid syndrome, characterised by chronic diarrhoea and/or flushing in the presence of systemically elevated levels of specific markers as serotonin or 5-hydroxyindolacetic acid. Skin manifestations include flushing of the face, neck and anterior surface of the chest but after repeated and prolonged relapses, the skin lesions become fixed, acquiring a bluish-red tint with telangiectasias. Patients may also develop pellagra skin symptoms including erythema, xerosis, scaling, hyperkeratosis and pigmentation, caused by a deficiency of tryptophan, due to its high consumption for serotonin synthesis.

This study addresses the need for precise histopathological assessment of liver biopsies in Metabolic dysfunction-Associated Steatohepatitis (MASH) cirrhosis, where assessing nuanced drug effects on fibrosis becomes pivotal. The study describes a framework for the development and validation of an Artificial Intelligence (AI) model, leveraging SHG/TPE microscopy along with insights from an expert hepatopathologist, to precisely annotate fibrous septa and nodules in liver biopsies in MASH cirrhosis. A total of 25 liver biopsies from the Belapectin trial (NCT04365868) were randomly selected for training, and an additional 10 for validation. Each biopsy underwent three sections: Smooth Muscle Actin (SMA) and Sirius Red (SR) staining for septa and nodule annotation by pathologists and an unstained section for SHG/TPE imaging and AI annotation using qSepta and qNodule algorithms. Re-training of qSepta and qNodule algorithms was executed based on pathologist annotations. Sensitivity and positive predictive value (PPV) were employed to evaluate concordance with pathologist annotations, both pre- and post-training and during validation. Post-re-training by pathologist annotations, the AI demonstrated improved sensitivity for qSepta annotations, achieving 91% post-training (versus 84% pre-training). Sensitivity for qSepta in the validation cohort also improved to 91%. Additionally, PPV significantly improved from 69% pre-training to 85% post-training and reached 94% during validation. For qNodule annotations, sensitivity increased from 82% post-training to 90% in the validation cohort, while the PPV was consistent at 95% across both training and validation cohorts.This study outlines a strategic framework for developing and validating an AI model tailored for precise histopathological assessment of MASH cirrhosis, using pathologist training and annotations. The outcomes emphasise the crucial role of disease-specific customisation of AI models, based on expert pathologist training, in improving accuracy and applicability in clinical trials, marking a step forward in understanding and addressing the histopathological evaluation of MASH cirrhosis.

African individuals with metabolic dysfunction-associated steatotic liver disease (MAFLD) may have unique genetic factors that influence the clinical manifestations of MAFLD. The paucity of both epidemiological data on MAFLD within Africa and the lack of genetic research thereof have disadvantaged the population, as extrapolated data out the region has been utilised to direct health care policy and management of the disease. This unique cohort of MAFLD individuals within Africa requires further epidemiological and genomic research to advance precision medicine within the realm of clinical hepatology. With the anticipated increase in non-communicable disease that sub-Saharan African may experience in the near future, a robust large study within Africa may provide insight as to whether MAFLD prevalence may be expected to significantly add to this impending health burden; furthermore, a genetic research component may provide insight into whether protective genetic variants are present or whether there is a lack of pathogenic variants, thereby allowing clinicians and policy strategists to have a better understanding of the disease prevalence and manifestations in African individuals. The aim of this publication was to review the current prevalence trends of MAFLD within Africa and the knowledge of the genetic landscape of MAFLD individuals of African descent.