Browsing by Subject "Fatty Liver"
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Item Acute alcoholic fatty liver syndromes(1965-09-16) UnknownItem Automated Quantification of Image-Derived Phenotypes and Integration with the Electronic Health Record at Scale in an Academic Biobank(2020-05-01T05:00:00.000Z) MacLean, Matthew Timothy; Hill, Joseph A.; de Lemos, James; Rader, DanielBACKGROUND: Radiographic images obtained during clinical care can yield a tremendous number of quantitative traits that facilitate translational research. Both liver fat and abdominal adipose mass are examples of quantitative traits that are highly relevant to human health and disease and can be quantitated from medical images such as CT scans. The Penn Medicine Biobank has generated genomic and biomarker data from >50,000 participants with consent to access EHR data. Among these patients, there are greater than 160,000 CT scans, representing over 19,000 patients from which these quantitative traits could be derived. However, manual review of imaging data is time-consuming, costly, and can produce variable results. OBJECTIVE: The goal of this research was to develop a fully automated pipeline to quantify hepatic fat and abdominal adipose mass from CT scans that could be run at scale on patients within the Penn Medicine Biobank. METHODS: We developed a fully automated image filtering and analysis pipeline to analyze CT imaging data. Deep learning networks were trained to identify the presence of IV contrast, delineate the borders of the liver and spleen, and detect visceral and subcutaneous fat. To identify CT studies, we queried our biobank of 52,441 patients for all non-contrast chest, abdomen, and all abdomen/pelvis scans and identified 161,748 CT scans from 19,624 patients. All scans were processed in our deep-learning pipeline in less than 96 hours using parallel processing with cloud-computing resources. From the imaging data, we extracted 12 different image-derived phenotypes that were used in association studies with the electronic health record (N>13000). We also performed genetic association studies (N>5000) on our CT-derived measure of liver fat (LF). Liver fat was defined as the difference in attenuation between the spleen and the liver. Receiver operator characteristic analysis of the liver fat metric was conducted by utilizing 135 patients who had both a CT scan as well as a liver biopsy. Finally, we performed principal component analysis to explore the interrelatedness of the image derived metrics in the context of the phenome. RESULTS: Each component of the algorithm was individually validated for accuracy. The first deep learning network (CNN1) functioned to identify IV contrast, and on a testing set of 400 (half with IV contrast), CNN1 classified 399 scans correctly. CNN2 was tasked with identifying the superior and inferior borders of the abdominal cavity and on a testing set of 100 scans was on average within one slice of the superior (1.01±1.11) and inferior (0.70±0.64) borders. Performance of CNN3, which was tasked with labeling liver, spleen, visceral and subcutaneous fat was assessed by computing region-of-interest area overlap ratios (Dice coefficients). Dice coefficients for a validation set of randomly selected CT scans showed high values for liver (0.95±0.02, n=20), spleen (0.92±0.07, n=20), abdominal compartment (0.98±0.01, n=10), subcutaneous fat (1.00±0.00, n=10), and visceral fat (0.99±0.01, n=10). After extracting the liver fat (LF) metric for all patients, LF had a mean of -6.4 ± 9.1 Hounsfield units. Association studies with billing codes in the electronic health record yielded many known associations for LF including with chronic liver disease, diabetes mellitus, obesity, and hypertension. A genetic association study showed significant associations with variants located in PNPLA3 and TM6SF2. ROC analysis using pathology data yielded an AUC value of 0.81 with a balanced cutoff value of -6 HU for LF. CONCLUSION: This paper presents a fully automated AI-based algorithm for the quantification of traits from medical imaging. This high-throughput algorithm was applied to over 160,000 scans to quantify 12 different traits and the results were integrated with phenome, genome, and pathology data in the Penn Medicine Biobank. This process is scalable, fast, and fault-tolerant and can power translational studies when integrated with clinical and genetic data.Item Fast food to fatty liver(2005-02-24) Horton, Jay D.Item Fatty liver: a potentially serious problem(1991-06-13) Combes, BurtonItem Hepatic Steatosis an emerging epidemic(2001-11-01) Horton, Jay D.Item Liver Fibrosis and Steatosis in HIV-Infected Patients: Impact of Race/Ethnicity, Gender, BMI, and ART(2019-04-02) Rucker, Danielle; Cutrell, James; Bedimo, Roger; Luque, AmnerisBACKGROUND: The advent of antiretroviral therapy (ART) led to a decline in morbidity and mortality related to AIDS and its related complications. With this decline, an increasing proportion of morbidity and mortality in people living with HIV (PLWH) is secondary to liver and cardiovascular disease. Previous studies have shown that PLWH have traditional risk factors for these diseases, such as obesity, as well as risk factors that are unique to their population, including direct metabolic effects of HIV and ART. Several factors, such as race, ethnicity, gender, and BMI, have been shown to have an impact on the course of liver steatosis and fibrosis in general population. The impact of these factors on the course of liver steatosis and fibrosis in the setting of hepatitis B and C co-infections in PLWH have been studied, but there is a paucity of literature detailing the impact in the absence of viral hepatitis co-infection. NAFLD, APRI, and FIB-4 scores have been shown to be effective noninvasive markers for clinically significant liver steatosis and fibrosis. However, these non-invasive markers have not been validated for use in patients without viral hepatitis co-infection. This study aims to determine if race, ethnicity, gender, BMI, and the specific ART regimen have a differential impact on non-invasive markers of liver steatosis and fibrosis in PLWH. OBJECTIVE: Determine if race, ethnicity, gender, BMI, and specific ART regimen will modulate changes in non-invasive markers of liver steatosis and fibrosis. METHODS: All patients initiating ART at the Parkland Memorial Hospital HIV clinic from 2009-2017 were analyzed. Exposure to ART was defined as concurrent receipt of at least two nucleoside reverse transcriptase inhibitor (NRTI) drugs plus at least one protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or integrase inhibitor (INSTI). The existing patient database includes demographics (notably, gender, race, and ethnicity), CD4 and HIV RNA levels, co-morbidities, laboratory values (most notably, liver function tests), ART regimen, and body mass index (BMI). An analysis of yearly changes in BMI was calculated based on specific ART drugs, and differences between groups stratified by gender or race/ethnicity were compared. For subjects who meet certain pre-determined liver function test minimums, non-invasive markers for liver fibrosis (APRI, NAFLD, and FIB-4 scores) will be utilized and trended over time. Manual chart extraction will be examined for patients with clinically-indicated imaging (abdominal ultrasound, computed tomography, or magnetic resonance imaging) to estimate the incidence and prevalence of liver fibrosis or steatosis in this population and to determine whether race/ethnicity or gender modifies these risks. RESULTS: The difference in yearly BMI change was statistically significant for the INSTI dolutegravir (DTG; p=<0.01) between Blacks and non-Hispanic whites (NHW) but not for any other ART drugs tested. The difference in yearly BMI change showed a trend for statistical significance for DTG (p=0.06) between Hispanics and NHW but not for any other ART drugs tested. The difference in yearly BMI change by ART drug in men versus women was statistically significant for atazanavir (ATV; p=0.03), darunavir (DRV;p=<0.01), lopinavir (LPV; p=0.03), and dolutegravir (DTG; p=<0.01) but not with elvitegravir (EVG; p=0.72). CONCLUSIONS AND NEXT STEPS: Our preliminary results indicate that particular ART drugs, principally the INSTI DTG, appear to be associated with greater BMI gains than other agents. Additionally, in PLWH on ART, women demonstrated greater BMI gains than men, and Blacks and Hispanics demonstrated greater BMI gains than NHW in our cohort. The next steps will be to analyze the trends of APRI, FIB-4, and NAFLD scores over time in our cohort as non-invasive markers of liver fibrosis and to determine the demographic, HIV, and ART-related factors associated with higher rates of liver fibrosis. We will also conduct a review of clinically-indicated abdominal imaging for evidence of hepatic fibrosis in a subset of our cohort to validate the use of these non-invasive markers in PLWH without viral hepatitis. Given that HIV has been transformed into a chronic disease and that PLWH are now living decades on these ART regimens, it is of paramount importance to determine the long-term metabolic and hepatic consequences of these medications to better inform patient care and practice guidelines. We believe that our large cohort of demographically diverse PLWH on contemporary ART regimens and with detailed clinical follow-up data offers an important population to further our understanding of these critical issues.Item Metabolic Regulation of Protein Phosphorylation and Acetylation(2018-07-12) Zhang, Menglu; Kohler, Jennifer J.; Tu, Benjamin; Nijhawan, Deepak; Yu, HongtaoCelluar metabolism can influence phosphorylation and acetylation modifications on proteins as part of an intricate network of cellular and organismal regulation. We have investigated one molecular mechanism through which protein phosphorylation and acetylation can be regulated based on metabolic status and how metabolic enzymes are regulated by nutrient availability. In the first part of this study, we report that a simple enzyme involved in acetate utilization, Acetyl-CoA synthetase 2 (ACSS2), promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. We reveal that mice lacking ACSS2 exhibit a significant reduction in body weight and hepatic steatosis in a diet-induced obesity model. ACSS2 deficiency reduces dietary lipid absorption by the intestine, and perturbs repartitioning and utilization of triglycerides from adipose tissue to the liver due to lowered expression of lipid transporters and fatty acid oxidation genes. In this manner, ACSS2 promotes the systemic storage or metabolism of fat according to the fed or fasted state. Targeting ACSS2 may therefore offer therapeutic benefit for the treatment of fatty liver disease. We also report that ACSS2 may play a critical role in the development of pancreatic cancer. We have demonstrated that ACSS2 expression in a KRas-driven mouse model of pancreatic ductal adenocarcinoma (PDAC) showed that ACSS2 was absent in normal pancreatic tissue but expressed at very high levels in precancerous lesions of PDAC. The absence of ACSS2 in mouse pancreatic cancer models reduced the tumor burdens, and ACSS2 expression is correlated with tumor size. These data indicate that ACSS2 has a potential function in the development of PDAC. The experiments reported in the first two chapters of this thesis were performed in close collaboration with a former postdoc in the lab, Dr. Zhiguang Huang. In the second part of the study, we report that methylation of Protein Phosphatase 2A (PP2A) may play a critical role in regulating cell growth and autophagy. We have reconstituted the methylation activity of leucine carboxyl methyltransferase 1 (LCMT-1) in vitro and determined the kinetic parameters of LCMT-1-catalyzed methylation of PP2A. We reveal that LCMT-1 might be a "SAM sensor" as it is very sensitive to the SAM/SAH ratio. Methionine deprivation study in cell lines revealed that methionine depletion boosts PP2A demethylation. We further conducted a high-throughput screen to identify potent and specific small molecule inhibitors of LCMT-1.Item NASH (non-alcoholic steatohepatitis)...: some answers, many questions(1999-02-04) Malet, Peter F.Item Nature, nurture, and nonalcoholic fatty liver disease(2014-05-16) Cohen, Jonathan C.Item Non-alcoholic fatty liver disease(2012-12-07) Browning, Jeffrey D.Due to publisher restrictions--the protocol file originally included a published article as a supplement--direct access to the article in this collection is not available within this collection. The abstract of that article is available through PubMed: https://pubmed.ncbi.nlm.nih.gov/22656328/Item Non-alcoholic fatty liver disease: what every clinician should know(2007-08-31) Browning, Jeffrey D.Item [UT Southwestern Medical Center News](2009-02-03) Shear, Kristen HollandItem [UT Southwestern Medical Center News](2011-04-19) Shear, Kristen HollandItem [UT Southwestern Medical Center News](2008-09-25) Siegfried, AmandaItem [UT Southwestern Medical Center News](2009-01-20) Ladson, LaKisha