Metabolic associated fatty liver disease (MAFLD) is the principal worldwide cause of liver disease and affects nearly a quarter of the global population. The objective of this work was to present the ...clinical practice guidelines of the Asian Pacific Association for the Study of the Liver (APASL) on MAFLD. The guidelines cover various aspects of MAFLD including its epidemiology, diagnosis, screening, assessment, and treatment. The document is intended for practical use and for setting the stage for advancing clinical practice, knowledge, and research of MAFLD in adults, with specific reference to special groups as necessary. The guidelines also seek to improve patient care and awareness of the disease and assist stakeholders in the decision-making process by providing evidence-based data. The guidelines take into consideration the burden of clinical management for the healthcare sector.
The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic ...immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.
There have been increasing reports of food-borne zoonotic transmission of hepatitis E virus (HEV) genotype 3, which causes chronic infections in immunosuppressed patients. We performed phylogenetic ...analyses of the HEV sequence (partial and full-length) from 1 patient from the Middle East who underwent liver transplantation, and compared it with other orthohepevirus A sequences. We found the patient to be infected by camelid HEV. This patient regularly consumed camel meat and milk, therefore camelid HEV, which is genotype 7, might infect human beings. Our finding links consumption of camel-derived food products to post-transplantation hepatitis E, which, if detected at early stages, can be cured with antiviral therapy and reduced administration of immunosuppressive agents.
Correspondence to Dr John Ong, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; jo401@cam.ac.uk Over 3000 healthcare workers (HCW) in China are suspected of ...having coronavirus disease 2019 (COVID-19) and over 1700 tested positive.1 These statistics underline the need for robust preventative measures against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Need to continue procedures: acute upper GI bleeding, oesophageal obstruction (foreign bodies, food bolus, pinhole stricture or cancer requiring urgent stenting), endoscopic vacuum therapy for perorations/leaks, acute cholangitis or jaundice secondary to biliary obstruction, acute biliary pancreatitis, cholangitis with stone and jaundice, infected pancreatic collections, walled-off pancreatic necrosis, urgent inpatient nutrition support (enteral feeding tubes), gastrointestinal obstruction needing urgent decompression or stenting. Surveillance polyp check, IBD, Barrett’s (unless high-risk neoplasia present), non-urgent enteroscopy, EUS for ‘benign’ indications—biliary dilatation, possible stones, submucosal lesions, pancreatic cysts without high-risk features. 2020. ‡‡Sociedad Española de Patología Digestiva (SEPD) (Updated SEPD recommendations on infection by the SARS-CoV-2 coronavirus.) APC, argon plasma coagulation; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; EUS, endoscopic ultrasonography; FIT, faecal immunochemical test; GAVE, gastric antral vascular ectasia; GI, gastrointestinal; IBD, inflammatory bowel disease; PEG, percutaneous endoscopic gastrostomy; POEM, peroral endoscopic myotomy; PPE, personal protective equipment; RFA, radio frequency ablation.Table 2 Summary of recommendations for periprocedural, intraprocedural and postprocedural recommendations including general advice Articles grouped by country:
The clinical presentation and outcomes of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma are unclear when compared with hepatocellular carcinoma due to other causes. We ...aimed to establish the prevalence, clinical features, surveillance rates, treatment allocation, and outcomes of NAFLD-related hepatocellular carcinoma.
In this systematic review and meta-analysis, we searched MEDLINE and Embase from inception until Jan 17, 2022, for articles in English that compared clinical features, and outcomes of NAFLD-related hepatocellular carcinoma versus hepatocellular carcinoma due to other causes. We included cross-sectional and longitudinal observational studies and excluded paediatric studies. Study-level data were extracted from the published reports. The primary outcomes were (1) the proportion of hepatocellular carcinoma secondary to NAFLD, (2) comparison of patient and tumour characteristics of NAFLD-related hepatocellular carcinoma versus other causes, and (3) comparison of surveillance, treatment allocation, and overall and disease-free survival outcomes of NAFLD-related versus non-NAFLD-related hepatocellular carcinoma. We analysed proportional data using a generalised linear mixed model. Pairwise meta-analysis was done to obtain odds ratio (OR) or mean difference, comparing NAFLD-related with non-NAFLD-related hepatocellular carcinoma. We evaluated survival outcomes using pooled analysis of hazard ratios.
Of 3631 records identified, 61 studies (done between January, 1980, and May, 2021; 94 636 patients) met inclusion criteria. Overall, the proportion of hepatocellular carcinoma cases secondary to NAFLD was 15·1% (95% CI 11·9–18·9). Patients with NAFLD-related hepatocellular carcinoma were older (p<0·0001), had higher BMI (p<0·0001), and were more likely to present with metabolic comorbidities (diabetes p<0·0001, hypertension p<0·0001, and hyperlipidaemia p<0·0001) or cardiovascular disease at presentation (p=0·0055) than patients with hepatocellular carcinoma due to other causes. They were also more likely to be non-cirrhotic (38·5%, 27·9–50·2 vs 14·6%, 8·7–23·4 for hepatocellular carcinoma due to other causes; p<0·0001). Patients with NAFLD-related hepatocellular carcinoma had larger tumour diameters (p=0·0087), were more likely to have uninodular lesions (p=0·0003), and had similar odds of Barcelona Clinic Liver Cancer stages, TNM stages, alpha fetoprotein concentration, and Eastern Cooperative Oncology Group (ECOG) performance status to patients with non-NAFLD-related hepatocellular carcinoma. A lower proportion of patients with NAFLD-related hepatocellular carcinoma underwent surveillance (32·8%, 12·0–63·7) than did patients with hepatocellular carcinoma due to other causes (55·7%, 24·0–83·3; p<0·0001). There were no significant differences in treatment allocation (curative therapy, palliative therapy, and best supportive care) between patients with NAFLD-related hepatocellular carcinoma and those with hepatocellular carcinoma due to other causes. Overall survival did not differ between the two groups (hazard ratio 1·05, 95% CI 0·92–1·20, p=0·43), but disease-free survival was longer for patients with NAFLD-related hepatocellular carcinoma (0·79, 0·63–0·99; p=0·044). There was substantial heterogeneity in most analyses (I2>75%), and all articles had low-to-moderate risk of bias.
NAFLD-related hepatocellular carcinoma is associated with a higher proportion of patients without cirrhosis and lower surveillance rates than hepatocellular carcinoma due to other causes. Surveillance strategies should be developed for patients with NAFLD without cirrhosis who are at high risk of developing hepatocellular carcinoma.
None.
SALL4,
which is expressed in fetal but not adult liver, is reexpressed in a subgroup of hepatocellular cancers associated with a poor prognosis. In mice, treatment aimed at inhibiting
SALL4
has ...antitumor effects.
Hepatocellular carcinoma is the third leading cause of cancer-related deaths globally. Although the epidemiologic risk factors for hepatocellular carcinoma are well known,
1
the molecular mechanisms underlying hepatocarcinogenesis are not well characterized. Elucidation of these mechanisms may allow identification of new candidates for therapeutic targeting. Although surgery, liver transplantation, and radiologic intervention may be viable options for patients with early-stage disease, the prognosis associated with advanced-stage hepatocellular carcinoma remains bleak.
2
Combination chemotherapy has not improved overall survival but has nonetheless been in wide use for many years because of its possible role in palliation. The need to understand the molecular pathogenesis . . .
The Adult Treatment panel III (ATP-III) criteria define metabolic syndrome as a group of conditions that together raise your risk of coronary heart disease, diabetes, stroke, and other serious health ...problems. Empirically, it is diagnosed when there are three out of five associated clinical diseases occurring together. 2 The MAFLD consensus attempt to patch this gap by defining the disease based on histological, imaging, or blood biomarker evidence of hepatic steatosis, in addition to the presence of at least one of the following: obesity, type 2 diabetes mellitus, or metabolic dysregulation. The latter in turn requires at least two criteria based on waist circumference, pre-diabetes, hypertension, hyperlipidemia, insulin resistance, or elevated high sensitivity C-reactive protein. 3 There are three unmet gaps in these approaches. (i) The criteria of MAFLD, though derived in consensus, are still empirically based and do not allow quantitative appreciation of accumulative metabolic risk. (ii) Waist circumference and obesity are but surrogate markers and do not take into account the more complex basis of ectopic fat deposition, lipotoxicity, and sarcopenia, features that are emerging as key pathological basis of insulin resistance driving metabolic complications. 4 (iii) Differences between population subgroups, stereotypically and simplistically classified as East versus West, require different subclassification of body mass index (BMI) and call into question whether these consensus criteria can be universally applied. 5 One good example is the entity of lean NAFLD, which has been described to be more common in Asia based on the observation that Asians develop metabolic complications at lower levels of BMI compared with their Western counterpart. 6 Many East vs.
Measuring liver stiffness only in patients with indeterminate or high nonalcoholic fatty liver disease (NAFLD) fibrosis scores (called a 2-step approach) was reported to reduce indeterminate or ...discordant results while maintaining the accuracy to identify patients with advanced fibrosis. We aimed to validate this approach using data collected from the Gut and Obesity in Asia Workgroup.
We performed a retrospective analysis of data from 759 patients with biopsy-proven NAFLD (24% with advanced fibrosis), seen at 10 centers in 9 countries in Asia, from 2006 through 2018. By using liver biopsies as the reference standard, we calculated percentages of misclassifications and indeterminate or discordant results from assessments made based on fibrosis scores (NAFLD fibrosis score NFS or Fibrosis-4 score) and liver stiffness measurements (LSMs), alone or in combination. The analysis was repeated using randomly selected subgroups with a different prevalence of advanced fibrosis (histologic fibrosis stage ≥F3).
In groups in which 3.7% and 10% of patients had advanced fibrosis, a 2-step approach (using the NFS followed by LSM only for patients with indeterminate or high NFS) and using a gray zone of 10 to 15 kPa for LSM, produced indeterminate or discordant results for 6.9% of patients and misclassified 2.7% of patients; only 25.6% of patients required LSM. In the group in which 10% of patients had advanced fibrosis, the same approach produced indeterminate or discordant results for 7.9% of patients and misclassified 6.6% of patients; only 27.4% of patients required LSM. In groups in which 24% and 50% of patients had advanced fibrosis, using LSM ≥10 kPa alone for the diagnosis of advanced fibrosis had the highest accuracy and misclassified 18.1% and 18.3% of patients, respectively. These results were similar when the Fibrosis-4 score was used in place of NFS.
In a retrospective analysis, we found that a 2-step approach using fibrosis scores followed by LSM most accurately detects advanced fibrosis in populations with a low prevalence of advanced fibrosis. However, LSM ≥10 kPa identifies patients with advanced fibrosis with the highest level of accuracy in populations with a high prevalence of advanced fibrosis.
ObjectiveAs the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. ...We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.DesignPatient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg−/− (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.ResultsSimilar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.ConclusionsOur work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.
PDF
