Browsing by Subject "Steatohepatitis"
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Item A comprehensive evaluation of candidate genetic polymorphisms in a large histologically characterized MASLD cohort using a novel framework(Wolters Kluwer, 2025-05-29) Hakim, Aaron; Lin, Kung-Hung; Schwantes-An, Tae-Hwi; Abreu, Marco; Tan, Jingyi; Guo, Xiuqing; Yates, Katherine P.; Lotta, Luca; Verweij, Niek; Loomba, Rohit; Kleiner, David E.; Schwimmer, Jeffrey B.; Rotter, Jerome I.; Chalasani, Naga P.; Medicine, School of MedicineBackground: There is a substantial heritable component to metabolic dysfunction-associated steatotic liver disease (MASLD), and several genetic variants that promote MASLD development or associate with its severity have been reported. These associations vary in terms of their effect size and degree of replication. Methods: We developed a framework to classify previously identified MASLD genetic polymorphisms into 4 tiers based on effect size and extent of replication in the literature. We tested the association between "tier 1" single-nucleotide polymorphisms (OR ≥1.5, replicated in >2 independent studies) and biopsy measures of MASLD severity in a large, well-characterized histologic cohort of MASLD patients (n=3094). Results: Across 19 "tier 1" variants reflecting 11 genetic loci, only those in the PNPLA3-SAMM50-PARVB locus showed significant associations with biopsy-proven fibrosis severity and NAFLD activity score; the highest risk was for the rs738409 p.I148M variant in PNPLA3. A genetic risk score based on "tier 1" variants, as well as a previously developed genetic risk score based on variants in PNPLA3, TM6SF2, and HSD17B13, were both associated with fibrosis and NAFLD activity score, but these results were driven entirely by PNPLA3 rs738409. Conclusions: Our study provides a framework to prioritize evaluation of genetic polymorphisms for future replication efforts and demonstrates that in a large case-only cohort, histologic severity of MASLD is only robustly associated with the presence of variation in PNPLA3 among known candidate genes. These findings may have implications for patient risk stratification based on the presence of PNPLA3 rs738409.Item Cardiolipin deficiency disrupts CoQ redox state and induces steatohepatitis(bioRxiv, 2024-10-10) Brothwell, Marisa J.; Cao, Guoshen; Maschek, J. Alan; Poss, Annelise M.; Peterlin, Alek D.; Wang, Liping; Baker, Talia B.; Shahtout, Justin L.; Siripoksup, Piyarat; Pearce, Quentinn J.; Johnson, Jordan M.; Finger, Fabian M.; Prola, Alexandre; Pellizzari, Sarah A.; Hale, Gillian L.; Manuel, Allison M.; Watanabe, Shinya; Miranda, Edwin R.; Affolter, Kajsa E.; Tippetts, Trevor S.; Nikolova, Linda S.; Choi, Ran Hee; Decker, Stephen T.; Patil, Mallikarjun; Catrow, J. Leon; Holland, William L.; Nowinski, Sara M.; Lark, Daniel S.; Fisher-Wellman, Kelsey H.; Mimche, Patrice N.; Evason, Kimberley J.; Cox, James E.; Summers, Scott A.; Gerhart-Hines, Zach; Funai, Katsuhiko; Dermatology, School of MedicineMetabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, cardiolipin (CL) was downregulated across four mouse models of MASLD. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous MASH with elevated mitochondrial electron leak. Loss of CL interfered with the ability of coenzyme Q (CoQ) to transfer electrons, promoting leak primarily at sites IIF and IIIQ0. Data from human liver biopsies revealed a highly robust correlation between mitochondrial CL and CoQ, co-downregulated with MASH. Thus, reduction in mitochondrial CL promotes oxidative stress and contributes to pathogenesis of MASH.Item Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease(Elsevier, 2023) Sanyal, Arun J.; Williams, Stephen A.; Lavine, Joel E.; Neuschwander-Tetri, Brent A.; Alexander, Leigh; Ostroff, Rachel; Biegel, Hannah; Kowdley, Kris V.; Chalasani, Naga; Dasarathy, Srinivasan; Diehl, Anna Mae; Loomba, Rohit; Hameed, Bilal; Behling, Cynthia; Kleiner, David E.; Karpen, Saul J.; Williams, Jessica; Jia, Yi; Yates, Katherine P.; Tonascia, James; Medicine, School of MedicineBackground & aims: Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD. Methods: Using modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4). Results: The AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified. Conclusions: Serum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD.Item Duodenal mucosal resurfacing for nonalcoholic fatty liver disease(Wiley, 2022-11-25) Shamseddeen, Hani; Vuppalanchi, Raj; Gromski, Mark A.; Medicine, School of MedicineContent available: Author Interview and Audio Recording.Item Glycogenosis is common in nonalcoholic fatty liver disease and is independently associated with ballooning, but lower steatosis and lower fibrosis(Wiley, 2021-05) Allende, Daniela S.; Gawrieh, Samer; Cummings, Oscar W.; Belt, Patricia; Wilson, Laura; Van Natta, Mark; Behling, Cynthia A.; Carpenter, Danielle; Gill, Ryan M.; Kleiner, David E.; Yeh, Mathew M.; Chalasani, Naga; Guy, Cynthia D.; Medicine, School of MedicineBackground/aims: Glycogen synthesis and storage are normal hepatocyte functions. However, glycogenosis, defined as excess hepatocyte glycogen visible by routine H&E light microscopy, has not been well characterized in nonalcoholic fatty liver disease (NAFLD). Methods: Glycogenosis in NAFLD liver biopsies was graded as "none", "focal" (in <50% of hepatocytes), or "diffuse" (in ≥50% of hepatocytes). Clinical and pathological variables associated with glycogenosis were assessed. 2047 liver biopsies were prospectively analysed. Results: In adults and children, any glycogenosis was present in 54% of cases; diffuse glycogenosis was noted in approximately 1/3 of cases. On multiple logistic regression analysis, adults with glycogenosis tended to be older (P = .003), female (P = .04), have higher serum glucose (P = .01), and use insulin (P = .02). Adults tended to have lower steatosis scores (P = .006) and lower fibrosis stages (P = .005); however, unexpectedly, they also tended to have more hepatocyte injury including ballooning (P = .003). On multiple logistic regression analysis, paediatric patients with glycogenosis were more likely to be Hispanic (P = .03), have lower body weight (P = .002), elevated triglycerides (P = .001), and a higher fasting glucose (P = .007). Paediatric patients with glycogenosis also had less steatosis (P < .001) than those without. Conclusions: Glycogenosis is common in adult and paediatric NAFLD, and is associated with clinical features of insulin resistance. Glycogenosis is important to recognize histologically because it may be misinterpreted as ballooning, and when diffuse, confusion with glycogen storage disorders or glycogenic hepatopathy must be avoided. The newly observed dichotomous relationship between glycogenosis and increased liver cell injury but decreased steatosis and fibrosis requires further study.Item Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals(Wiley, 2013) Masuoka, Howard C.; Chalasani, Naga; Medicine, School of MedicineNonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. NAFLD is a spectrum ranging from simple steatosis, which is relatively benign hepatically, to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type 2 diabetes. The diagnosis of NAFLD requires imaging evidence of hepatic steatosis in the absence of competing etiologies including significant alcohol consumption. Liver biopsy remains the gold standard for diagnosing NASH and for determining prognosis. Weight loss remains a cornerstone of treatment. Weight loss of ~5% is believed to improve steatosis, whereas ~10% weight loss is necessary to improve steatohepatitis. A number of pharmacologic therapies have been investigated to treat NASH, and agents such as vitamin E and thiazolidinediones have shown promise in select patient subgroups.Item An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis(Wolters Kluwer, 2020-08) Arab, Juan P.; Sehrawat, Tejasav S.; Simonetto, Douglas A.; Verma, Vikas K.; Feng, Dechun; Tang, Tom; Dreyer, Kevin; Yan, Xiaoqiang; Daley, William L.; Sanyal, Arun; Chalasani, Naga; Radaeva, Svetlana; Yang, Liu; Vargas, Hugo; Ibacache, Mauricio; Gao, Bin; Gores, Gregory J.; Malhi, Harmeet; Kamath, Patrick S.; Shah, Vijay H.; Medicine, School of MedicineBackground and aims: Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH. Approach and results: A phase-2 dose-escalating study was carried out. F-652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42. Conclusions: F-652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.Item Physical Activity and Nonalcoholic Fatty Liver Disease: A Roundtable Statement from the American College of Sports Medicine(Wolters Kluwer, 2023) Stine, Jonathan G.; Long, Michelle T.; Corey, Kathleen E.; Sallis, Robert E.; Allen, Alina M.; Armstrong, Matthew J.; Conroy, David E.; Cuthbertson, Daniel J.; Duarte-Rojo, Andres; Hallsworth, Kate; Hickman, Ingrid J.; Kappus, Matthew R.; Keating, Shelley E.; Pugh, Christopher J. A.; Rotman, Yaron; Simon, Tracey L.; Vilar-Gomez, Eduardo; Wai-Sun Wong, Vincent; Schmitz, Kathryn H.; Medicine, School of MedicineAlthough physical activity (PA) is crucial in the prevention and clinical management of nonalcoholic fatty liver disease, most individuals with this chronic disease are inactive and do not achieve recommended amounts of PA. There is a robust and consistent body of evidence highlighting the benefit of participating in regular PA, including a reduction in liver fat and improvement in body composition, cardiorespiratory fitness, vascular biology, and health-related quality of life. Importantly, the benefits of regular PA can be seen without clinically significant weight loss. At least 150 min of moderate or 75 min of vigorous intensity PA are recommended weekly for all patients with nonalcoholic fatty liver disease, including those with compensated cirrhosis. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. In this roundtable document, the benefits of PA are discussed, along with recommendations for 1) PA assessment and screening; 2) how best to advise, counsel, and prescribe regular PA; and 3) when to refer to an exercise specialist.Item Signal Transduction and Molecular Regulation in Fatty Liver Disease(Mary Ann Liebert, 2021) Dong, Xiaocheng Charlie; Chowdhury, Kushan; Huang, Menghao; Kim, Hyeong Geug; Biochemistry and Molecular Biology, School of MedicineSignificance: Fatty liver disease is a major liver disorder in the modern societies. Comprehensive understanding of the pathophysiology and molecular mechanisms is essential for the prevention and treatment of the disease. Recent Advances: Remarkable progress has been made in the recent years in basic and translational research in the field of fatty liver disease. Multiple signaling pathways have been implicated in the development of fatty liver disease, including AMP-activated protein kinase, mechanistic target of rapamycin kinase, endoplasmic reticulum stress, oxidative stress, inflammation, transforming growth factor β, and yes1-associated transcriptional regulator/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). In addition, critical molecular regulations at the transcriptional and epigenetic levels have been linked to the pathogenesis of fatty liver disease. Critical Issues: Some critical issues remain to be solved so that research findings can be translated into clinical applications. Robust and reliable biomarkers are needed for diagnosis of different stages of the fatty liver disease. Effective and safe molecular targets remain to be identified and validated. Prevention strategies require solid scientific evidence and population-wide feasibility. Future Directions: As more data are generated with time, integrative approaches are needed to comprehensively understand the disease pathophysiology and mechanisms at multiple levels from population, organismal system, organ/tissue, to cell. The interactions between genes and environmental factors require deeper investigation for the purposes of prevention and personalized treatment of fatty liver disease.Item The global prevalence and impact of steatotic liver disease and viral infections: A systematic review and meta-analysis(Wolters Kluwer, 2025-04-14) Li, Jiajing; Zhou, Jiahua; Li, Pengfei; Wang, Yining; Ridderhof, Nathalie; Al-Tawfiq, Jaffar A.; Brouwer, Willem Pieter; Chen, Kan; de Knegt, Robert J.; Peppelenbosch, Maikel P.; Hansen, Bettina E.; Engel, Maarten F. M.; Zheng, Ming-Hua; Memish, Ziad A.; Eslam, Mohammed; Janssen, Harry L. A.; Pan, Qiuwei; Ayada, Ibrahim; Medicine, School of MedicineBackground: Steatotic liver disease (SLD) affects ~30% of adults worldwide. The global population is continuously threatened by epidemic and endemic viral diseases. This study aims to thoroughly examine the interaction between SLD and major viral diseases. Methods: We systematically searched databases from inception to April 2, 2024, for observational studies recording viral-infected adult patients with eligible data on the presence of hepatic steatosis. Results: Six hundred thirty-six eligible studies were included in the analysis of SLD prevalence. Among patients with monoinfections, the highest SLD prevalence was observed in those infected with HCV at 49% (95% CI: 47%-51%), followed by SARS-CoV-2 (39%, 95% CI [34%-44%]), HIV (39%, 95% CI [33%-44%]), and HBV (36%, 95% CI [32%-40%]). Additionally, co-infections, such as HCV-HIV and HBV-HCV, exhibit even higher SLD prevalence. The prevalence of steatohepatitis is particularly high in HIV-infected (24%, 95% CI: 17%-30%) and HCV-infected (18%, 95% CI: 13%-24%) populations. The co-existence of SLD with viral infections was associated not only with the progression of liver disease but also with more severe outcomes of the infections and poorer responses to antiviral treatment. The combination of cardiometabolic risk factors and viral-associated and host factors contributes to the higher risk of SLD in viral-infected populations. Conclusions: SLD is highly prevalent in viral-infected populations, and the reciprocal interactions between SLD and viral diseases exacerbate both conditions, leading to poorer patient outcomes in general.