The role of dietary modification in the prevention and management of metabolic dysfunction-associated fatty liver disease: An international multidisciplinary expert consensus.

Metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), has become the leading cause of chronic liver disease worldwide. Optimal dietary intervention strategies for MAFLD are not standardized. This study aimed to achieve consensus on prevention of MAFLD through dietary modification. A multidisciplinary panel of 55 international experts, including specialists in hepatology, gastroenterology, dietetics, endocrinology and other medical specialties from six continents collaborated in a Delphi-based consensus development process. The consensus statements covered aspects ranging from epidemiology to mechanisms, management, and dietary recommendations for MAFLD. The recommended dietary strategies emphasize adherence to a balanced diet with controlled energy intake and personalized nutritional interventions, such as calorie restriction, high-protein, or low-carbohydrate diets. Specific dietary advice encouraged increasing the consumption of whole grains, plant-based proteins, fish, seafood, low-fat or fat-free dairy products, liquid plant oils, and deeply colored fruits and vegetables. Concurrently, it advised reducing the intake of red and processed meats, saturated and trans fats, ultra-processed foods, added sugars, and alcohol. Additionally, maintaining the Mediterranean or DASH diet, minimizing sedentary behavior, and engaging in regular physical activity are recommended. These consensus statements lay the foundation for customized dietary guidelines and proposing avenues for further research on nutrition and MAFLD.

Helicobacter pylori infection is associated with liver fibrosis in patients with obesity undergoing bariatric surgery.

Background: Obesity is a significant risk factor for metabolic-associated steatotic liver disease (MASLD). The association between Helicobacter pylori (HP) infection and liver fibrosis has not been fully elucidated in patients with obesity and MASLD. Methods: This observational retrospective study included clinical and biochemical parameters of patients with obesity undergoing bariatric surgery. HP infection was confirmed by gastric endoscopy, and liver biopsies were performed during surgery. Bivariate and logistic regression analyses were employed to evaluate independent associations with liver fibrosis and steatosis by biopsy. Results: The mean age of the subjects was 42 ± 10 years, with 84.7% being women, and they had a mean BMI of 42.97 ± 7.56 kg/m2. Overall, 41.7% of patients had an HP infection. Multiple logistic regression models were conducted to assess the association between HP infection, liver steatosis, and fibrosis by biopsy. HP infection was independently associated with liver fibrosis [OR = 3.164 (95% CI 1.011-9.900)]. Conclusion: Biopsy findings associated HP infection with increased liver fibrosis.

Bilirubin Molecular Species Play an Important Role in the Pathophysiology of Acute-on-Chronic Liver Failure.

Bilirubin plays a key role in early diagnosis, prognosis, and prevention of liver diseases. Unconjugated bilirubin (UCB) requires conversion to a water-soluble form through liver glucuronidation, producing monoglucuronide (BMG) or diglucuronide bilirubin (BDG) for bile excretion. This study aimed to assess the roles of bilirubin's molecular species-UCB, BMG, and BDG-in diagnosing and understanding the pathogenesis of liver cirrhosis in patients with acute-on-chronic liver failure (ACLF), compensated liver cirrhosis (LC) patients, and healthy individuals. The study included patients with ACLF and compensated LC of diverse etiologies, along with healthy controls. We collected laboratory and clinical data to determine the severity and assess mortality. We extracted bilirubin from serum samples to measure UCB, BMG, and BDG using liquid chromatography-mass spectrometry (LC-MS). The quantification of bilirubin was performed by monitoring the mass charge (m/z) ratio. Of the 74 patients assessed, 45 had ACLF, 11 had LC, and 18 were healthy individuals. Among ACLF patients, the levels of molecular species of bilirubin were UCB 19.69 µmol/L, BMG 47.71 µmol/L, and BDG 2.120 µmol/L. For compensated cirrhosis patients, the levels were UCB 11.29 µmol/L, BMG 1.49 µmol/L, and BDG 0.055 µmol/L, and in healthy individuals, the levels were UCB 6.42 µmol/L, BMG 0.52 µmol/L, and BDG 0.028 µmol/L. The study revealed marked elevations in the bilirubin species in individuals with ACLF compared to those with compensated cirrhosis and healthy controls, underscoring the progression of liver dysfunction. The correlation of BMG and BDG levels with commonly used inflammatory markers suggests a relationship between bilirubin metabolism and systemic inflammation in ACLF.

Exploring the Logic and Conducting a Comprehensive Evaluation of the Adiponectin Receptor Agonists AdipoRon and AdipoAI's Impacts on Bone Metabolism and Repair-A Systematic Review.

INTRODUCTION: Adiponectin replacement therapy shows promising outcomes in various diseases, especially for bone-related disorders. Challenges in using the complete protein have led to alternative approaches, with AdipoRon and AdipoAI emerging as extensively researched drug candidates. Their influence on models of bone-related disorders has progressed considerably but there has been no review of their effectiveness in modulating bone metabolism and repair. METHOD: This systematic review seeks to address this knowledge gap. Based on preclinical evidence from PubMed, EMBASE, and COCHRANE, ten studies were included following PRISMA guidelines. The JBI Checklist Critical Appraisal Tool assessed the quality of this systematic review. The studies encompassed various animal models, addressing bone defects, osseointegration, diabetes-associated periodontitis, fracture repair, growth retardation, and diabetes-associated peri-implantitis. RESULT: AdipoRon and AdipoAI demonstrated effectiveness in modulating bone metabolism and repair through diverse pathways, including the activation of AdipoR1/APPL1, inhibition of F-actin ring formation, suppression of IκB-α phosphorylation, p65 nuclear translocation and Wnt5a-Ror2 signaling pathway, reduction of CCL2 secretion and expression, regulation of autophagy via LC3A/B expression, modulation of SDF-1 production, activation of the ERK-1/2 signaling pathway, modulation of bone integration-related markers and osteokines such as RANKL, BMP-2, OPG, OPN, and Runx2, inhibition of RANKL in osteoblasts, and inhibition of podosome formation via the activation of AMPK. CONCLUSION: While preclinical studies show promise, human trials are crucial to confirm the clinical safety and effectiveness of AdipoRon and AdipoAI. Caution is necessary due to potential off-target effects, especially in bone therapy with multi-target approaches. Structural biology and computational methods can help predict and understand these effects.

Global burden of metabolic diseases, 1990-2021.

BACKGROUND: Common metabolic diseases, such as type 2 diabetes mellitus (T2DM), hypertension, obesity, hypercholesterolemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), have become a global health burden in the last three decades. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD) data enables the first insights into the trends and burdens of these metabolic diseases from 1990 to 2021, highlighting regional, temporal and differences by sex. METHODS: Global estimates of disability-adjusted life years (DALYs) and deaths from GBD 2021 were analyzed for common metabolic diseases (T2DM, hypertension, obesity, hypercholesterolemia, and MASLD). Age-standardized DALYs (mortality) per 100,000 population and annual percentage change (APC) between 1990 and 2021 were estimated for trend analyses. Estimates are reported with uncertainty intervals (UI). RESULTS: In 2021, among five common metabolic diseases, hypertension had the greatest burden (226 million [95 % UI: 190-259] DALYs), whilst T2DM (75 million [95 % UI: 63-90] DALYs) conferred much greater disability than MASLD (3.67 million [95 % UI: 2.90-4.61]). The highest absolute burden continues to be found in the most populous countries of the world, particularly India, China, and the United States, whilst the highest relative burden was mostly concentrated in Oceania Island states. The burden of these metabolic diseases has continued to increase over the past three decades but has varied in the rate of increase (1.6-fold to 3-fold increase). The burden of T2DM (0.42 % [95 % UI: 0.34-0.51]) and obesity (0.26 % [95 % UI: 0.17-0.34]) has increased at an accelerated rate, while the rate of increase for the burden of hypertension (-0.30 % [95 % UI: -0.34 to -0.25]) and hypercholesterolemia (-0.33 % [95 % UI: -0.37 to -0.30]) is slowing. There is no significant change in MASLD over time (0.05 % [95 % UI: -0.06 to 0.17]). CONCLUSION: In the 21st century, common metabolic diseases are presenting a significant global health challenge. There is a concerning surge in DALYs and mortality associated with these conditions, underscoring the necessity for a coordinated global health initiative to stem the tide of these debilitating diseases and improve population health outcomes worldwide.

Impact of peptic ulcer bleeding on the in-hospital outcomes of cirrhotic patients with acute gastrointestinal bleeding: an international multicenter study.

OBJECTIVES: Peptic ulcer is the most common source of non-variceal bleeding. However, it remains controversial whether the outcomes of cirrhotic patients with peptic ulcer bleeding differ from those with variceal bleeding. METHODS: Cirrhotic patients with acute gastrointestinal bleeding (AGIB) who underwent endoscopy and had an identifiable source of bleeding were retrospectively screened from an international multicenter cohort. Logistic regression analyses were performed to explore the impact of peptic ulcer bleeding on in-hospital death and 5-day failure to control bleeding. Propensity score matching (PSM) analysis was performed by matching age, gender, Child-Pugh score, and model for end-stage liver disease score between the peptic ulcer bleeding and variceal bleeding groups. RESULTS: Overall, 1535 patients were included, of whom 73 (4.7%) had peptic ulcer bleeding. Multivariate logistic regression analyses showed that peptic ulcer bleeding was not independently associated with in-hospital death (OR = 2.169, p = 0.126) or 5-day failure to control bleeding (OR = 1.230, p = 0.680). PSM analyses demonstrated that both in-hospital mortality (9.7% vs. 6.3%, p = 0.376) and rate of 5-day failure to control bleeding (6.9% vs. 5.4%, p = 0.787) were not significantly different between the two groups. CONCLUSIONS: The impact of peptic ulcer bleeding on the in-hospital outcomes of cirrhotic patients is similar to that of variceal bleeding.

In this international multicenter study, we included 1535 patients with acute gastrointestinal bleeding (AGIB) and divided them into peptic ulcer bleeding and variceal bleeding groups. We found that only a minority of AGIB episodes in cirrhotic patients was attributed to peptic ulcer. Additionally, after adjusting for the severity of liver dysfunction, the in-hospital mortality and the rate of 5-day failure to control bleeding should be similar between cirrhotic patients with peptic ulcer bleeding and those with variceal bleeding.

The myth of the stigma of fatty liver: What does the evidence show?

Recent efforts to reclassify non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are intended to divert attention to the metabolic basis of the disease rather than to alcohol consumption. This reclassification recognizes the role of obesity, sedentary lifestyles and poor dietary habits in the development of the disease, leading to a better understanding of its etiology. Nevertheless, the transition has posed its own challenges, particularly with regard to communication between patient and healthcare professional. Many healthcare professionals report difficulty in explaining the nuanced concepts, especially the term "steatosis". In addition, the change in terminology has not yet removed the stigma, with ongoing debates about the appropriateness of the terms "fatty" and "steatotic". Surveys suggest that while "obesity" may be perceived as more stigmatizing, the medical term "steatotic liver disease" is not considered as stigmatizing, indicating a disconnect in perceptions between healthcare professionals and patients.

Metabolic dysfunction associated fatty liver disease in healthy weight individuals.

Metabolic dysfunction associated fatty liver disease (MAFLD) is an increasing public health problem, affecting one third of the global population. Contrary to conventional wisdom, MAFLD is not exclusive to obese or overweight individuals. Epidemiological studies have revealed a remarkable prevalence among healthy weight individuals, leading investigations into the genetic, lifestyle, and dietary factors that contribute to the development of MAFLD in this population. This shift in perspective requires reconsideration of preventive strategies, diagnostic criteria and therapeutic approaches tailored to address the unique characteristics of MAFLD healthy weight individuals. It also underscores the importance of widespread awareness and education, within the medical community and among the general population, to promote a more inclusive understanding of liver metabolic disorders. With this review, we aim to provide a comprehensive exploration of MAFLD in healthy weight individuals, encompassing epidemiological, pathophysiological, and clinical aspects.

Why MASLD Lags Behind MAFLD: A Critical Analysis of Diagnostic Criteria Evolution in Metabolic Dysfunction-Associated Liver Diseases.

Emerging in the 1800s under the label "fat in the liver" and later gaining prominence in the 1980 as non-alcoholic fatty liver disease (NAFLD), the disease predominantly attributed to metabolic dysfunction presents a formidable health issue marked by substantial morbidity and mortality. It was 2020 when a change of one letter "NAFLD" to metabolic dysfunction-associated fatty liver disease "MAFLD" linked with the change in the definition and diagnostic criteria began a new controversy around the globe. Metabolic dysfunction-associated fatty liver disease (MAFLD) criteria represent a substantial departure from previous diagnostic measures of NAFLD, and provide the first set of positive criteria for diagnosis of the disease in adults and children that emphasise the key attribute of metabolic dysfunction in the pathogenesis, and acknowledges that the disease is a continuum across the life span. In 2023, an adapted version of the diagnostic criteria of MAFLD was proposed to define a slightly modified term; metabolic dysfunction-associated steatotic liver disease (MASLD). The MASLD criteria did not provide any conceptual advantage, and emerging evidence suggests that it actually performs worse than the MAFLD criteria. This raises the intriguing question of why MASLD was unable to take advantage of being second? In this review, we will explore the possible reasons for this unique case and highlight the current evidence supporting the use of MAFLD instead of MASLD in defining metabolic dysfunction-associated fatty liver diseases.

A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease.

BACKGROUND: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11. METHODS: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members. RESULTS: A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%). CONCLUSIONS: This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision.

An international multidisciplinary consensus on pediatric metabolic dysfunction-associated fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts. METHODS: A group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management. FINDINGS: In round 1, we received 65 surveys from 35 countries and analyzed these results, which informed us that 73.3% of respondents agreed with 20 draft statements while 23.8% agreed somewhat. The mean percentage of agreement or somewhat agreement increased to 80.85% and 15.75%, respectively, in round 2. The final statements covered a wide range of topics related to epidemiology, pathophysiology, and strategies for screening and managing pediatric MAFLD. CONCLUSIONS: The consensus statements and recommendations developed by an international expert panel serve to optimize clinical outcomes and improve the quality of life for children and adolescents with MAFLD. These findings emphasize the need for standardized approaches in diagnosing and treating pediatric MAFLD. FUNDING: This work was funded by the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-014), the Wuxi Taihu Talent Plan (DJTD202106), and the Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021007).

Underlying Mechanisms behind the Brain-Gut-Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update.

Metabolic-associated fatty liver disease (MAFLD) includes several metabolic dysfunctions caused by dysregulation in the brain-gut-liver axis and, consequently, increases cardiovascular risks and fatty liver dysfunction. In MAFLD, type 2 diabetes mellitus, obesity, and metabolic syndrome are frequently present; these conditions are related to liver lipogenesis and systemic inflammation. This study aimed to review the connection between the brain-gut-liver axis and MAFLD. The inflammatory process, cellular alterations in hepatocytes and stellate cells, hypercaloric diet, and sedentarism aggravate the prognosis of patients with MAFLD. Thus, to understand the modulation of the physiopathology of MAFLD, it is necessary to include the organokines involved in this process (adipokines, myokines, osteokines, and hepatokines) and their clinical relevance to project future perspectives of this condition and bring to light new possibilities in therapeutic approaches. Adipokines are responsible for the activation of distinct cellular signaling in different tissues, such as insulin and pro-inflammatory cytokines, which is important for balancing substances to avoid MAFLD and its progression. Myokines improve the quantity and quality of adipose tissues, contributing to avoiding the development of MAFLD. Finally, hepatokines are decisive in improving or not improving the progression of this disease through the regulation of pro-inflammatory and anti-inflammatory organokines.

Chronic Hepatitis C Virus Infection, Extrahepatic Disease and the Impact of New Direct-Acting Antivirals.

Chronic hepatitis C virus infection is an important cause of liver cirrhosis, hepatocellular carcinoma and death. Furthermore, it is estimated that about 40-70% of patients develop non-hepatic alterations in the course of chronic infection. Such manifestations can be immune-related conditions, lymphoproliferative disorders and metabolic alterations with serious adverse events in the short and long term. The introduction of new Direct-Acting Antivirals has shown promising results, with current evidence indicating an improvement and remission of these conditions after a sustained virological response.

MAFLD predicts cardiovascular disease risk better than MASLD.

BACKGROUND AND AIM: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed as an alternative for the validated definition of metabolic dysfunction-associated fatty liver disease (MAFLD). We compared the abilities of MAFLD and MASLD to predict the risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: Six thousand and ninety six participants from the 2017 to 2020 National Health and Nutrition Examination Survey cohort who received a thorough medical health check-up were chosen for the study. The associations between fatty liver status and coronary risk surrogates, such as 10-year ASCVD risk and self-reported cardiovascular events, were analysed. RESULTS: MAFLD and MASLD were identified in 2911 (47.7%) and 2758 (45.2%) patients, respectively. MAFLD (odds ratio [OR]: 2.14, 95% confidence interval [CI], 1.78-2.57, p < .001) was more strongly independently associated with high ASCVD risk than MASLD (OR: 1.82, 95% CI, 1.52-2.18, p < .001) was in comparison with the absence of each condition. However, compared with MAFLD, MASLD alone was not associated with increased ASCVD risk. Multiple logistic regression revealed that MAFLD alone was significantly more strongly associated with a high risk of ASCVD (OR: 2.82; 95% CI: 1.13-7.01; p < .03) than MASLD alone. CONCLUSIONS: Although both MAFLD and MASLD were associated with different ASCVD risks, MAFLD predicted the ASCVD risk better than MASLD. The higher predictive ability of MAFLD compared to MASLD was attributed to metabolic dysfunction rather than moderate alcohol use.

From prediction to prevention: Machine learning revolutionizes hepatocellular carcinoma recurrence monitoring.

In this editorial, we comment on the article by Zhang et al entitled Development of a machine learning-based model for predicting the risk of early postoperative recurrence of hepatocellular carcinoma. Hepatocellular carcinoma (HCC), which is characterized by high incidence and mortality rates, remains a major global health challenge primarily due to the critical issue of postoperative recurrence. Early recurrence, defined as recurrence that occurs within 2 years posttreatment, is linked to the hidden spread of the primary tumor and significantly impacts patient survival. Traditional predictive factors, including both patient- and treatment-related factors, have limited predictive ability with respect to HCC recurrence. The integration of machine learning algorithms is fueled by the exponential growth of computational power and has revolutionized HCC research. The study by Zhang et al demonstrated the use of a groundbreaking preoperative prediction model for early postoperative HCC recurrence. Chall-enges persist, including sample size constraints, issues with handling data, and the need for further validation and interpretability. This study emphasizes the need for collaborative efforts, multicenter studies and comparative analyses to validate and refine the model. Overcoming these challenges and exploring innovative approaches, such as multi-omics integration, will enhance personalized oncology care. This study marks a significant stride toward precise, effi-cient, and personalized oncology practices, thus offering hope for improved patient outcomes in the field of HCC treatment.