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).

Chronic exposure to ethanol alters the expression of miR-155, miR-122 and miR-217 in alcoholic liver disease in an adult zebrafish model.

AIM: The aim of this study was to evaluate the hepatic and circulating expression of miR-155, miR-122 and miR-217 in a model of chronic exposure to ethanol in adult zebrafish. METHODS: Wild-type adult zebrafish were divided into two groups (n = 281): an EG (exposed to 0.5% v/v Ethanol in aquarium water) and a CG (without ethanol). After 28 days the animals were euthanized, followed by histopathological analysis, quantification of lipids, triglycerides and inflammatory cytokines in liver tissue. miR-155, miR-122 and miR-217 gene expression was quantified in liver tissue and serum. RESULTS: We observed hepatic lesions and increased accumulation of hepatic lipids in the EG. The expression of il-1ß was higher in the EG, but there were no differences in il-10 and tnf-α between groups. In the liver, expression of miR-122 and miR-155 was higher in the EG. The circulating expression of miR-155 and miR-217 was significantly higher in the EG. CONCLUSION: Chronic exposure to ethanol in zebrafish leads to altered hepatic and circulating expression of miR-155, miR-122 and miR-217. This confirms its potential as a biomarker and therapeutic target.

Gut Dysbiosis and Increased Intestinal Permeability Drive microRNAs, NLRP-3 Inflammasome and Liver Fibrosis in a Nutritional Model of Non-Alcoholic Steatohepatitis in Adult Male Sprague Dawley Rats.

BACKGROUND/AIM: The interactions between the gut and liver have been described in the progression of non-alcoholic steatohepatitis (NASH). The aim of this study was to develop an experimental nutritional model of NASH simulating metabolic changes occurring in humans. MATERIALS AND METHODS: Adult male Sprague Dawley rats were randomized into two groups: controls (standard diet) and intervention (high-fat and choline-deficient diet) for 16 weeks, each experimental group with 10 animals. Biochemical analysis, hepatic lipid content, microRNAs, inflammatory, gut permeability markers and gut microbiota were measured. RESULTS: Animals in the intervention group showed significantly higher delta Lee index (p=0.017), abdominal circumference (p<0.001), abdominal adipose tissue (p<0.001) and fresh liver weight (p<0.001), as well as higher serum levels of alanine aminotransferase (p=0.010), glucose (p=0.013), total cholesterol (p=0.033), LDL cholesterol (p=0.011), and triglycerides (p=0.011), and lower HDL cholesterol (p=0.006) compared to the control group. Higher TLR4 (p=0.041), TLR9 (p=0.033), MyD88 (p=0.001), Casp1 (p<0.001), NLPR3 (p=0.019), liver inflammation index interleukin (IL)-1ß/IL10 (p<0.001), IL6/IL10 (p=0.002) and TNFα/IL10 (p=0.001) were observed in the intervention group, and also lower permeability markers Ocln (p=0.003) and F11r (p=0.041). Gene expression of miR-122 increased (p=0.041) and miR-145 (p=0.010) decreased in the intervention group. Liver steatosis, inflammation and fibrosis, along with collagen fiber deposition increment (p<0.001), were seen in the intervention group. Regarding gut microbiota, Bray-Curtis dissimilarity index and number of operational taxonomic units were significantly different (p<0.001) between the groups. Composition of the gut microbiota showed a significant correlation with histopathological score of NAFLD (r=0.694) and index IL-1ß/IL-10 (r=0.522). CONCLUSION: This experimental model mimicking human NASH demonstrated gut and liver interaction, with gut microbiota and intestinal permeability changes occurring in parallel with systemic and liver inflammation, miRNAs regulation and liver tissue damage.

Hypothermia is better than ischemic preconditioning for preventing early hepatic ischemia/reperfusion in rats.

BACKGROUND: Topical hypothermia (TH) and ischemic preconditioning (IPC) are used to decrease I/R injury. The efficacy of isolated or combined use of TH and IPC in the liver regarding inflammation and cytoprotection in early ischemia/reperfusion (I/R) injury needs to be evaluated. MATERIAL AND METHODS: Wistar rats underwent 70% liver ischemia for 90 min followed by 120 min of reperfusion. Livers of animals allocated in the sham, normothermic ischemia (NI), IPC, TH, and TH+IPC groups were collected for molecular analyses by ELISA and Western blot, aiming to compare proinflammatory, anti-inflammatory, and antioxidant profiles. RESULTS: Compared with NI, TH presented decreased tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 and IL-12 concentrations and increased IL-10 levels. TH animals displayed lower inducible nitric oxide synthase (iNOS) and higher endothelial nitric oxide synthase (eNOS) expressions. NAD(P)H-quinone oxidoreductase-1(NQO1) expression was also lower with TH. Isolated IPC and NI were similar regarding all these markers. TH+IPC was associated with decreased IL-12 concentration and reduced iNOS and NQO1 expressions, similarly to isolated TH. Expression of Kelch-like ECH-associated protein (Keap)-1 was increased and expression of nuclear and cytosolic nuclear erythroid 2-related factor 2 (Nrf2) was decreased with TH+IPC vs. NI. CONCLUSION: TH was the most effective method of protection against early I/R injury. Isolated IPC entailed triggering of second-line antioxidant defense enzymes. Combined TH+IPC seemed to confer no additional advantage over isolated TH in relation to the inflammatory process, but had the advantage of completely avoid second-line antioxidant defense enzymes.

UGT1A1, SLCO1B1, and SLCO1B3 polymorphisms vs. neonatal hyperbilirubinemia: is there an association?

BACKGROUND: Jaundice is a physiological phenomenon; however, severe hyperbilirubinemia occurs in only 5 to 6% of the healthy newborn population. It has been suggested that genetic variation could enhance the risk of hyperbilirubinemia when coexpressed with other icterogenic conditions. METHODS: The study included newborns with a gestational age of greater than 35 wk and weights greater than 2,000 g with indications for phototherapy. The polymorphisms from UGT1A1 (rs8175347), SLCO1B1 (rs4149056 and rs2306283), and SLCO1B3 (rs17680137 and rs2117032) were analyzed by capillary electrophoresis and hydrolysis probes. RESULTS: A total of 167 hyperbilirubinemic infants and 247 control subjects were enrolled. The gender, ABO incompatibility, birth weight, and gestational age differed between the groups, but the allelic and genotypic frequency of the polymorphisms from SLCO1B genes did not. In logistic regression, the ABO incompatibility, gestational age, and polymorphic T allele of rs2117032 remained in the model. The presence of this polymorphism seemed to provide protection from hyperbilirubinemia. The individuals who were homozygous for the G allele of rs2306283 and who were glucose 6-phosphate-dehydrogenase deficient were more frequent among the cases. CONCLUSION: Although genetic variation accounts for a good part of this condition, the association between different polymorphisms and environmental factors has yet to be explained.

Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats.

CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7) hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.

Comparison between handgrip strength, subjective global assessment, and prognostic nutritional index in assessing malnutrition and predicting clinical outcome in cirrhotic outpatients.

OBJECTIVE: This study compared three methods of assessing malnutrition in cirrhotics and correlated nutritional status with clinical outcome. METHODS: This cross-sectional study evaluated nutritional status by subjective global assessment (SGA), prognostic nutritional index (PNI), and handgrip strength (HG) in outpatients with cirrhosis (n = 50) and two control groups with hypertension (n = 46) and functional gastrointestinal disorders (n = 49). Patients with cirrhosis were followed for 1 y to verify the incidence of major complications, the need for transplantation, and death. RESULTS: Among patients with cirrhosis, 88% were Child-Pugh A and only 12% were Child-Pugh B. Among these, prevalences of malnutrition were 28% by SGA, 18.7% by PNI, and 63% by HG (P < 0.05). HG, but not SGA or PNI, predicted a poorer clinical outcome in patients with cirrhosis because major complications such as uncontrolled ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome developed in 65.5% of malnourished patients versus 11.8% of well-nourished ones (P < 0.05). No significant differences by any method were seen between the two groups regarding liver transplantation or death. CONCLUSIONS: There was a high prevalence of malnutrition in cirrhotic outpatients, especially when assessed by HG, which was superior to SGA and PNI in this study. HG was the only technique that predicted a significant incidence of major complications in 1 y in undernourished cirrhotic patients.