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Journal of Hepatology Oct 2023Current hepatocellular carcinoma (HCC) risk scores do not reflect changes in HCC risk resulting from liver disease progression/regression over time. We aimed to develop... (Observational Study)
Observational Study
BACKGROUND & AIMS
Current hepatocellular carcinoma (HCC) risk scores do not reflect changes in HCC risk resulting from liver disease progression/regression over time. We aimed to develop and validate two novel prediction models using multivariate longitudinal data, with or without cell-free DNA (cfDNA) signatures.
METHODS
A total of 13,728 patients from two nationwide multicenter prospective observational cohorts, the majority of whom had chronic hepatitis B, were enrolled. aMAP score, as one of the most promising HCC prediction models, was evaluated for each patient. Low-pass whole-genome sequencing was used to derive multi-modal cfDNA fragmentomics features. A longitudinal discriminant analysis algorithm was used to model longitudinal profiles of patient biomarkers and estimate the risk of HCC development.
RESULTS
We developed and externally validated two novel HCC prediction models with a greater accuracy, termed aMAP-2 and aMAP-2 Plus scores. The aMAP-2 score, calculated with longitudinal data on the aMAP score and alpha-fetoprotein values during an up to 8-year follow-up, performed superbly in the training and external validation cohorts (AUC 0.83-0.84). The aMAP-2 score showed further improvement and accurately divided aMAP-defined high-risk patients into two groups with 5-year cumulative HCC incidences of 23.4% and 4.1%, respectively (p = 0.0065). The aMAP-2 Plus score, which incorporates cfDNA signatures (nucleosome, fragment and motif scores), optimized the prediction of HCC development, especially for patients with cirrhosis (AUC 0.85-0.89). Importantly, the stepwise approach (aMAP -> aMAP-2 -> aMAP-2 Plus) stratified patients with cirrhosis into two groups, comprising 90% and 10% of the cohort, with an annual HCC incidence of 0.8% and 12.5%, respectively (p <0.0001).
CONCLUSIONS
aMAP-2 and aMAP-2 Plus scores are highly accurate in predicting HCC. The stepwise application of aMAP scores provides an improved enrichment strategy, identifying patients at a high risk of HCC, which could effectively guide individualized HCC surveillance.
IMPACT AND IMPLICATIONS
In this multicenter nationwide cohort study, we developed and externally validated two novel hepatocellular carcinoma (HCC) risk prediction models (called aMAP-2 and aMAP-2 Plus scores), using longitudinal discriminant analysis algorithm and longitudinal data (i.e., aMAP and alpha-fetoprotein) with or without the addition of cell-free DNA signatures, based on 13,728 patients from 61 centers across mainland China. Our findings demonstrated that the performance of aMAP-2 and aMAP-2 Plus scores was markedly better than the original aMAP score, and any other existing HCC risk scores across all subsets, especially for patients with cirrhosis. More importantly, the stepwise application of aMAP scores (aMAP -> aMAP-2 -> aMAP-2 Plus) provides an improved enrichment strategy, identifying patients at high risk of HCC, which could effectively guide individualized HCC surveillance.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; alpha-Fetoproteins; Cohort Studies; Cell-Free Nucleic Acids; Liver Cirrhosis; Hepatitis B, Chronic
PubMed: 37302583
DOI: 10.1016/j.jhep.2023.05.039 -
Digestion 2024Functional endoscopy signifies a significant advancement in gastrointestinal examination, integrating motor function assessments alongside routine endoscopy findings.... (Review)
Review
BACKGROUND
Functional endoscopy signifies a significant advancement in gastrointestinal examination, integrating motor function assessments alongside routine endoscopy findings. Traditional gastrointestinal endoscopy primarily focuses on the detection of early-stage cancer by identifying morphological changes within the gastrointestinal tract. These alterations include modifications in lumen structure, color tone, and surface patterns, which can be diagnosed using endoscopic images that assess these morphological changes. In contrast, functional endoscopy aims to dynamically evaluate the peristaltic movements of the digestive tract and the presence or movement of reflux of digestive fluids during the endoscopic procedure. It also seeks to identify morphological changes such as hiatal hernias, as observed in conventional endoscopy. Consequently, relying solely on endoscopic images proves inadequate for diagnosis, necessitating continuous observation of these dynamic movements.
SUMMARY
The endoscopic pressure study integrated system (EPSIS) serves as an exemplar of functional endoscopy. It incorporates a stress test to assess the functionality of the lower esophageal sphincter (LES) through intragastric insufflation. A crucial element of EPSIS evaluation is the identification of the scope holding sign (SHS), which signifies LES contraction. EPSIS also encompasses the observation of esophageal peristaltic waves and the auditory detection of burping, providing a comprehensive diagnostic approach while observing the sphincter from a retroflex view on the stomach side. By integrating these dynamic findings, functional endoscopy offers an efficient method for diagnosing functional gastrointestinal diseases, such as gastroesophageal reflux disease (GERD).
KEY MESSAGES
Functional endoscopy combines motor function assessments with traditional endoscopy, enhancing the diagnostic capabilities of gastrointestinal examinations. Traditional endoscopy focuses on identifying morphological changes, while functional endoscopy evaluates dynamic movements, reflux, and sphincter functionality. EPSIS exemplifies functional endoscopy, featuring a stress test and the SHS for LES contraction assessment. EPSIS provides a comprehensive approach to diagnose GERD by integrating dynamic observations.
Topics: Humans; Gastroesophageal Reflux; Endoscopy, Gastrointestinal; Esophageal Sphincter, Lower; Hernia, Hiatal; Manometry
PubMed: 38008079
DOI: 10.1159/000534831 -
Gastroenterology Oct 2023The purpose of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review is to provide clinicians with guidance on the use of... (Review)
Review
DESCRIPTION
The purpose of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review is to provide clinicians with guidance on the use of noninvasive tests (NITs) in the evaluation and management of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD affects nearly 30% of the global population and is a growing cause of end-stage liver disease and liver-related health care resource utilization. However, only a minority of all patients with NAFLD experience a liver-related outcome. It is therefore critically important for clinicians to assess prognosis and identify those with increased risk of disease progression and negative clinical outcomes at the time of initial assessment. It is equally important to assess disease trajectory over time, particularly in response to currently available therapeutic approaches. The reference standard for assessment of prognosis and disease monitoring is histologic examination of liver biopsy specimens. There are, however, many limitations of liver biopsies and their reading that have limited their use in routine practice. The utilization of NITs facilitates risk stratification of patients and longitudinal assessment of disease progression for patients with NAFLD. This clinical update provides best practice advice based on a review of the literature on the utilization of NITs in the management of NAFLD for clinicians. Accordingly, a combination of available evidence and consensus-based expert opinion, without formal rating of the strength and quality of the evidence, was used to develop these best practice advice statements.
METHODS
This Expert Review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. These best practice advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these best practice advice statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: NITs can be used for risk stratification in the diagnostic evaluation of patients with NAFLD. BEST PRACTICE ADVICE 2: A Fibrosis 4 Index score <1.3 is associated with strong negative predictive value for advanced hepatic fibrosis and may be useful for exclusion of advanced hepatic fibrosis in patients with NAFLD. BEST PRACTICE ADVICE 3: A combination of 2 or more NITs combining serum biomarkers and/or imaging-based biomarkers is preferred for staging and risk stratification of patients with NAFLD whose Fibrosis 4 Index score is >1.3. BEST PRACTICE ADVICE 4: Use of NITs in accordance with manufacturer's specifications (eg, not in patients with ascites or pacemakers) can minimize risk of discordant results and adverse events. BEST PRACTICE ADVICE 5: NITs should be interpreted with context and consideration of pertinent clinical data (eg, physical examination, biochemical, radiographic, and endoscopic) to optimize positive predictive value in the identification of patients with advanced fibrosis. BEST PRACTICE ADVICE 6: Liver biopsy should be considered for patients with NIT results that are indeterminate or discordant; conflict with other clinical, laboratory, or radiologic findings; or when alternative etiologies for liver disease are suspected. BEST PRACTICE ADVICE 7: Serial longitudinal monitoring using NITs for assessment of disease progression or regression may inform clinical management (ie, response to lifestyle modification or therapeutic intervention). BEST PRACTICE ADVICE 8: Patients with NAFLD and NITs results suggestive of advanced fibrosis (F3) or cirrhosis (F4) should be considered for surveillance of liver complications (eg, hepatocellular carcinoma screening and variceal screening per Baveno criteria). Patients with NAFLD and NITs suggestive of advanced hepatic fibrosis (F3) or (F4), should be monitored with serial liver stiffness measurement; vibration controlled transient elastography; or magnetic resonance elastography, given its correlation with clinically significant portal hypertension and clinical decompensation.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Liver; Disease Progression; Biomarkers
PubMed: 37542503
DOI: 10.1053/j.gastro.2023.06.013 -
Nature Communications Nov 2023Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs)...
Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs) constitute the prominant population of immune cells in tumor tissues, contributing to the formation of CSC niches and a suppressive immune microenvironment. Here, we report that high expression of inhibitor of differentiation 1 (ID1) in TAMs correlates with poor outcome in patients with colorectal cancer (CRC). ID1 expressing macrophages maintain cancer stemness and impede CD8 T cell infiltration. Mechanistically, ID1 interacts with STAT1 to induce its cytoplasmic distribution and inhibits STAT1-mediated SerpinB2 and CCL4 transcription, two secretory factors responsible for cancer stemness inhibition and CD8 T cell recruitment. Reducing ID1 expression ameliorates CRC progression and enhances tumor sensitivity to immunotherapy and chemotherapy. Collectively, our study highlights the pivotal role of ID1 in controlling the protumor phenotype of TAMs and paves the way for therapeutic targeting of ID1 in CRC.
Topics: Humans; Macrophages; Immunotherapy; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; T-Lymphocytes; Tumor Microenvironment; Inhibitor of Differentiation Protein 1
PubMed: 37996458
DOI: 10.1038/s41467-023-43548-w -
Journal of Hepatology Sep 2023An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the...
BACKGROUND & AIMS
An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community.
METHODS
Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy.
RESULTS
The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of 'agree' responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement ('agree' + 'somewhat agree'); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% 'agree'), 13 priorities had <80% 'agree', with greater reliance on 'somewhat agree' to achieve >90% combined agreement.
CONCLUSIONS
Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community's efforts to advance and accelerate responses to this widespread and fast-growing public health threat.
IMPACT AND IMPLICATIONS
An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat.
Topics: Child; Humans; Adolescent; Non-alcoholic Fatty Liver Disease; Public Health; Research; Global Health
PubMed: 37353401
DOI: 10.1016/j.jhep.2023.04.035 -
The Lancet. Gastroenterology &... Sep 2023Data are scarce regarding the development of hepatic decompensation in patients with non-alcoholic fatty liver disease (NAFLD) with and without type 2 diabetes. We aimed... (Meta-Analysis)
Meta-Analysis
Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis.
BACKGROUND
Data are scarce regarding the development of hepatic decompensation in patients with non-alcoholic fatty liver disease (NAFLD) with and without type 2 diabetes. We aimed to assess the risk of hepatic decompensation in people with NAFLD with and without type 2 diabetes.
METHODS
We did a meta-analysis of individual participant-level data from six cohorts in the USA, Japan, and Turkey. Included participants had magnetic resonance elastography between Feb 27, 2007, and June 4, 2021. Eligible studies included those with liver fibrosis characterisation by magnetic resonance elastography, longitudinal assessment for hepatic decompensation and death, and included adult patients (aged ≥18 years) with NAFLD, for whom data were available regarding the presence of type 2 diabetes at baseline. The primary outcome was hepatic decompensation, defined as ascites, hepatic encephalopathy, or variceal bleeding. The secondary outcome was the development of hepatocellular carcinoma. We used competing risk regression using the Fine and Gray subdistribution hazard ratio (sHR) to compare the likelihood of hepatic decompensation in participants with and without type 2 diabetes. Death without hepatic decompensation was a competing event.
FINDINGS
Data for 2016 participants (736 with type 2 diabetes; 1280 without type 2 diabetes) from six cohorts were included in this analysis. 1074 (53%) of 2016 participants were female with a mean age of 57·8 years (SD 14·2) years and BMI of 31·3 kg/m (SD 7·4). Among 1737 participants (602 with type 2 diabetes and 1135 without type 2 diabetes) with available longitudinal data, 105 participants developed hepatic decompensation over a median follow-up time of 2·8 years (IQR 1·4-5·5). Participants with type 2 diabetes had a significantly higher risk of hepatic decompensation at 1 year (3·37% [95% CI 2·10-5·11] vs 1·07% [0·57-1·86]), 3 years (7·49% [5·36-10·08] vs 2·92% [1·92-4·25]), and 5 years (13·85% [10·43-17·75] vs 3·95% [2·67-5·60]) than participants without type 2 diabetes (p<0·0001). After adjustment for multiple confounders (age, BMI, and race), type 2 diabetes (sHR 2·15 [95% CI 1·39-3·34]; p=0·0006) and glycated haemoglobin (1·31 [95% CI 1·10-1·55]; p=0·0019) were independent predictors of hepatic decompensation. The association between type 2 diabetes and hepatic decompensation remained consistent after adjustment for baseline liver stiffness determined by magnetic resonance elastography. Over a median follow-up of 2·9 years (IQR 1·4-5·7), 22 of 1802 participants analysed (18 of 639 with type 2 diabetes and four of 1163 without type 2 diabetes) developed incident hepatocellular carcinoma. The risk of incident hepatocellular carcinoma was higher in those with type 2 diabetes at 1 year (1·34% [95% CI 0·64-2·54] vs 0·09% [0·01-0·50], 3 years (2·44% [1·36-4·05] vs 0·21% [0·04-0·73]), and 5 years (3·68% [2·18-5·77] vs 0·44% [0·11-1·33]) than in those without type 2 diabetes (p<0·0001). Type 2 diabetes was an independent predictor of hepatocellular carcinoma development (sHR 5·34 [1·67-17·09]; p=0·0048).
INTERPRETATION
Among people with NAFLD, the presence of type 2 diabetes is associated with a significantly higher risk of hepatic decompensation and hepatocellular carcinoma.
FUNDING
National Institute of Diabetes and Digestive and Kidney Diseases.
Topics: Adult; Humans; Female; Adolescent; Middle Aged; Male; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Liver Neoplasms; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage
PubMed: 37419133
DOI: 10.1016/S2468-1253(23)00157-7 -
Journal of Hepatology Jul 2024Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along... (Review)
Review
Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.
Topics: Humans; Acute Kidney Injury; Liver Cirrhosis; Hepatorenal Syndrome; Ascites; Consensus
PubMed: 38527522
DOI: 10.1016/j.jhep.2024.03.031 -
Cleveland Clinic Journal of Medicine Jun 2024Gastroparesis is a heterogeneous motility disorder characterized by nausea, vomiting, and postprandial fullness. Its diagnosis requires objective documentation of... (Review)
Review
Gastroparesis is a heterogeneous motility disorder characterized by nausea, vomiting, and postprandial fullness. Its diagnosis requires objective documentation of delayed gastric emptying of solid food and exclusion of mechanical obstruction. Its epidemiology is unclear, and the main causes are diabetes mellitus and idiopathic disease. Cardinal symptoms often co-occur. Management involves nutritional assessment, dietary changes, drug evaluation, glycemic control (for patients with diabetes mellitus), and symptom relief. In this review, we explore challenges nongastroenterologists may encounter and how they can use current recommendations to manage patients with gastroparesis.
Topics: Gastroparesis; Humans; Gastric Emptying
PubMed: 38830702
DOI: 10.3949/ccjm.91a.23078 -
Gut Jun 2024Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on...
OBJECTIVE
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further.
DESIGN
Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice.
RESULTS
These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (), 6q, 8p, 16q, 9p (), 17p () and 13q (), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the and amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials.
CONCLUSION
HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Hepatitis B virus; Humans; Virus Integration; Animals; Mice; Male; Middle Aged; Female; Adult; Whole Genome Sequencing; DNA Copy Number Variations; Aged
PubMed: 38395437
DOI: 10.1136/gutjnl-2023-330414 -
Ugeskrift For Laeger May 2024This review investigates that, in 2023, fatty liver disease underwent a name change to "steatotic liver disease" (SLD). SLD now includes metabolic dysfunction-associated... (Review)
Review
This review investigates that, in 2023, fatty liver disease underwent a name change to "steatotic liver disease" (SLD). SLD now includes metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and metabolic and alcohol-related liver disease (MetALD). The renaming aims to better incorporate alcohol intake and metabolic risk factors into disease classification and to diminish the stigma associated with the previous nomenclature. Early identification of the patient's aetiology is important for the prognosis which can be improved by interventions against the causative risk factors.
Topics: Humans; Terminology as Topic; Risk Factors; Fatty Liver; Fatty Liver, Alcoholic; Alcohol Drinking; Non-alcoholic Fatty Liver Disease; Liver Diseases, Alcoholic
PubMed: 38808766
DOI: 10.61409/V12230778