343 results on '"Elizabeth M Brunt"'
Search Results
2. Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial.
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Victor J Navarro, Steven H Belle, Massimo D'Amato, Nezam Adfhal, Elizabeth M Brunt, Michael W Fried, K Rajender Reddy, Abdus S Wahed, Stephen Harrison, and Silymarin in NASH and C Hepatitis (SyNCH) Study Group
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Medicine ,Science - Abstract
The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease and may be a treatment for NASH due to its antioxidant properties. We aimed to assess the safety and efficacy of higher than customary doses of silymarin in non-cirrhotic patients with NASH. This exploratory randomized double-blind placebo controlled multicenter Phase II trial tested a proprietary standardized silymarin preparation (Legalon®, Rottapharm|Madaus, Mylan) and was conducted at 5 medical centers in the United States. Eligible adult patients had liver biopsy within 12 months showing NASH without cirrhosis with NAFLD Activity Score (NAS) ≥4 per site pathologist's assessment. Participants were randomized to Legalon® 420 mg, 700 mg, or placebo t.i.d. for 48 weeks. The primary endpoint was histological improvement ≥2 points in NAS. Of 116 patients screened, 78 were randomized. There were no significant differences in adverse events among the treatment groups. After 48-50 weeks, 4/27 (15%) in the 700 mg dose, 5/26 (19%) participants randomized to 420 mg, and 3/25 (12%) of placebo recipients reached the primary endpoint (p = 0.79) among all randomized participants, indicating no benefit from silymarin in the intention to treat analysis Review by a central pathologist demonstrated that a substantial number of participants (49, 63%) did not meet histological entry criteria and that fibrosis stage improved most in the placebo treated group, although not significantly different from other groups. Silymarin (Legalon®) at the higher than customary doses tested in this study is safe and well tolerated. The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered the study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin treated patients, and the unanticipated effect of placebo on fibrosis indicate the need for additional clinical trials. Trial Registration: clinicaltrials.gov, Identifier: NCT00680407.
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- 2019
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3. Multi-SNP analysis of GWAS data identifies pathways associated with nonalcoholic fatty liver disease.
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Qing-Rong Chen, Rosemary Braun, Ying Hu, Chunhua Yan, Elizabeth M Brunt, Daoud Meerzaman, Arun J Sanyal, and Kenneth Buetow
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Medicine ,Science - Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease; the histological spectrum of which ranges from steatosis to steatohepatitis. Nonalcoholic steatohepatitis (NASH) often leads to cirrhosis and development of hepatocellular carcinoma. To better understand pathogenesis of NAFLD, we performed the pathway of distinction analysis (PoDA) on a genome-wide association study dataset of 250 non-Hispanic white female adult patients with NAFLD, who were enrolled in the NASH Clinical Research Network (CRN) Database Study, to investigate whether biologic process variation measured through genomic variation of genes within these pathways was related to the development of steatohepatitis or cirrhosis. Pathways such as Recycling of eIF2:GDP, biosynthesis of steroids, Terpenoid biosynthesis and Cholesterol biosynthesis were found to be significantly associated with NASH. SNP variants in Terpenoid synthesis, Cholesterol biosynthesis and biosynthesis of steroids were associated with lobular inflammation and cytologic ballooning while those in Terpenoid synthesis were also associated with fibrosis and cirrhosis. These were also related to the NAFLD activity score (NAS) which is derived from the histological severity of steatosis, inflammation and ballooning degeneration. Eukaryotic protein translation and recycling of eIF2:GDP related SNP variants were associated with ballooning, steatohepatitis and cirrhosis. Il2 signaling events mediated by PI3K, Mitotic metaphase/anaphase transition, and Prostanoid ligand receptors were also significantly associated with cirrhosis. Taken together, the results provide evidence for additional ways, beyond the effects of single SNPs, by which genetic factors might contribute to the susceptibility to develop a particular phenotype of NAFLD and then progress to cirrhosis. Further studies are warranted to explain potential important genetic roles of these biological processes in NAFLD.
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- 2013
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4. Role of choline deficiency in the Fatty liver phenotype of mice fed a low protein, very low carbohydrate ketogenic diet.
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Rebecca C Schugar, Xiaojing Huang, Ashley R Moll, Elizabeth M Brunt, and Peter A Crawford
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Medicine ,Science - Abstract
Though widely employed for clinical intervention in obesity, metabolic syndrome, seizure disorders and other neurodegenerative diseases, the mechanisms through which low carbohydrate ketogenic diets exert their ameliorative effects still remain to be elucidated. Rodent models have been used to identify the metabolic and physiologic alterations provoked by ketogenic diets. A commonly used rodent ketogenic diet (Bio-Serv F3666) that is very high in fat (~94% kcal), very low in carbohydrate (~1% kcal), low in protein (~5% kcal), and choline restricted (~300 mg/kg) provokes robust ketosis and weight loss in mice, but through unknown mechanisms, also causes significant hepatic steatosis, inflammation, and cellular injury. To understand the independent and synergistic roles of protein restriction and choline deficiency on the pleiotropic effects of rodent ketogenic diets, we studied four custom diets that differ only in protein (5% kcal vs. 10% kcal) and choline contents (300 mg/kg vs. 5 g/kg). C57BL/6J mice maintained on the two 5% kcal protein diets induced the most significant ketoses, which was only partially diminished by choline replacement. Choline restriction in the setting of 10% kcal protein also caused moderate ketosis and hepatic fat accumulation, which were again attenuated when choline was replete. Key effects of the 5% kcal protein diet - weight loss, hepatic fat accumulation, and mitochondrial ultrastructural disarray and bioenergetic dysfunction - were mitigated by choline repletion. These studies indicate that synergistic effects of protein restriction and choline deficiency influence integrated metabolism and hepatic pathology in mice when nutritional fat content is very high, and support the consideration of dietary choline content in ketogenic diet studies in rodents to limit hepatic mitochondrial dysfunction and fat accumulation.
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- 2013
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5. Liver pathology in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: vasculopathic disease beyond nodular regenerative hyperplasia
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Pooja Khonde, Deyali Chatterjee, Madonna Bogacki, M. Kathryn Liszewski, Andria L. Ford, Jonathan J. Miner, John P. Atkinson, and Elizabeth M. Brunt
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Pathology and Forensic Medicine - Published
- 2023
6. List of Contributors
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N. Volkan Adsay, Venancio A.F. Alves, Quentin M. Anstee, Olca Basturk, Christopher O.C. Bellamy, Elizabeth M. Brunt, Alastair D. Burt, Andrew D. Clouston, James M. Crawford, Linda D. Ferrell, Raul S. Gonzalez, Maria Guido, Gillian L. Hale, Stefan G. Hübscher, Prodromos Hytiroglou, Sanjay Kakar, David E. Kleiner, Ansgar W. Lohse, Alessandra Mangia, Yasuni Nakanuma, Valerie Paradis, Antonello Pietrangelo, Alberto Quaglia, Eve A. Roberts, Luigi M. Terracciano, Neil D. Theise, Dina G. Tiniakos, Michael Torbenson, Kay Washington, Aileen Wee, Matthew M. Yeh, Sherif R. Zaki, Yoh Zen, and Jessica Zucman-Rossi
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- 2024
7. Hepatic Nuclear Receptor Expression Associates with Features of Histology in Pediatric Nonalcoholic Fatty Liver Disease
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Erin E. Elbel, Joel E. Lavine, Michael Downes, Mark Van Natta, Ruth Yu, Jeffrey B. Schwimmer, Cynthia Behling, Elizabeth M. Brunt, James Tonascia, and Ronald Evans
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adults. This study examined the relationship between hepatic nuclear receptor (NR) expression and histologic features of NAFLD. Drugs targeting a variety of NRs for nonalcoholic steatohepatitis (NASH) are in clinical trials. Liver messenger RNA was isolated from 40 children (10‐19 years) undergoing end‐of‐treatment biopsy in the Treatment of NAFLD in Children (TONIC) trial. High‐throughput quantitative polymerase chain reaction assayed NR messenger RNA. Cluster analysis was used to group 36 NRs, and NR levels were related to histologic measures of specific NAFLD features. Cluster analysis determined five groupings of NRs. Significant (P < 0.05) differential expressions of specific NRs associated with histologic measures include farnesoid X receptor alpha and retinoic acid receptor (RARβ and RARβ) for steatosis; estrogen receptor alpha (ERα) and peroxisome proliferator‐activated receptor gamma 3 (PPARγ3) for hepatocellular ballooning; ER and PPARγ2 for lobular inflammation; PPARα/δ/γ1/γ2, ERα, constitutive androstane receptor, chicken ovalbumin upstream promoter transcription factor 1, RARα, RARβ1, retinoid X receptor, pregnane X receptor, thyroid hormone receptors α and β, and nuclear receptor related‐1 for fibrosis; and ERα and RARβ/β1/α for diagnosis of NASH. Conclusion: Differential expression of specific NRs correlates with histologic severity of specific NAFLD features. These NRs are pleiotropic transactivators regulating basal metabolic functions and inflammatory responses. Derangement of activity of these receptors in NAFLD provides a rationale for exploiting their ability with receptor‐specific ligands to ameliorate NASH and its consequences.
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- 2018
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8. Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers
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Zachary L Skidmore, Jason Kunisaki, Yiing Lin, Kelsy C Cotto, Erica K Barnell, Jasreet Hundal, Kilannin Krysiak, Vincent Magrini, Lee Trani, Jason R Walker, Robert Fulton, Elizabeth M Brunt, Christopher A Miller, Richard K Wilson, Elaine R Mardis, Malachi Griffith, William Chapman, and Obi L Griffith
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Cancer Research ,Carcinoma, Hepatocellular ,Liver ,Liver Neoplasms ,Genetics ,Humans ,Genomics ,Transcriptome ,Molecular Biology ,Article - Abstract
BackgroundLiver cancer is the second leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) risk factors include chronic hepatitis, cirrhosis, and alcohol abuse, whereby tumorigenesis is induced through inflammation and subsequent fibrotic response. However, a subset of HCC arises in non-cirrhotic livers. We characterized the genomic and transcriptomic landscape of non-cirrhotic HCC to identify features underlying the disease’s development and progression.MethodsWhole genome and transcriptome sequencing was performed on 30 surgically resectable tumors comprised of primarily of non-cirrhotic HCC and adjacent normal tissue. Using somatic variants, capture reagents were created and employed on an additional 87 cases of mixed cirrhotic/non-cirrhotic HCC. Cases were analyzed to identify viral integrations, single nucleotide variants (SNVs), insertions and deletions (INDELS), copy number variants, loss of heterozygosity, gene fusions, structural variants, and differential gene expression.ResultsWe detected 3,750 SNVs/INDELS and extensive CNVs and expression changes. Recurrent TERT promoter mutations occurred in >52% of non-cirrhotic discovery samples. Frequently mutated genes included TP53, CTNNB1, and APOB. Cytochrome P450 mediated metabolism was significantly downregulated. Structural variants were observed at MACROD2, WDPCP and NCKAP5 in >20% of samples. Furthermore, NR1H4 fusions involving gene partners EWSR1, GNPTAB, and FNIP1 were detected and validated in 2 non-cirrhotic samples.ConclusionGenomic analysis can elucidate mechanisms that may contribute to non-cirrhotic HCC tumorigenesis. The comparable mutational landscape between cirrhotic and non-cirrhotic HCC supports previous work suggesting a convergence at the genomic level during disease progression. It is therefore possible genomic-based treatments can be applied to both HCC subtypes with progressed disease.HighlightsNon-cirrhotic HCC genomically resembles cirrhotic HCCComprehensive genome- and transcriptome-wide profiling allows detection of novel structural variants, fusions, and undiagnosed viral infectionsNR1H4 fusions may represent a novel mechanism for tumorigenesis in HCCNon-cirrhotic HCC is characterized by genotoxic mutational signatures and dysregulated liver metabolismClinical history and comprehensive omic profiling incompletely explain underlying etiologies for non-cirrhotic HCC highlighting the need for further researchShort DescriptionThis study characterizes the genomic landscape of hepatocellular carcinomas (HCCs) in non-cirrhotic livers. Using 117 HCCs tumor/normal pairs, we identified 3,750 SNVs/INDELS with high variant frequency in TERT, TP53, CTNNB1, and APOB. CYP450 was significantly downregulated and many structural variants were observed. This characterization could assist in elucidating non-cirrhotic HCC tumorigenesis.
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- 2022
9. SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma
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Marianna B. Ruzinova, Changqing Ma, Elizabeth M. Brunt, Charles W. Goss, Neeta Vachharajani, William C. Chapman, and Ta-Chiang Liu
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Keratin-19 ,Carcinoma, Hepatocellular ,Stem Cells ,Liver Neoplasms ,SOX9 Transcription Factor ,Epithelial Cell Adhesion Molecule ,Prognosis ,Pathology and Forensic Medicine ,Antigens, Neoplasm ,Biomarkers, Tumor ,Humans ,Surgery ,RNA, Messenger ,Anatomy - Abstract
Various stem cell markers (eg, epithelial cell adhesion molecule [EpCAM], cytokeratin 19 [K19]) have been reported as predictors of poor prognosis in hepatocellular carcinoma (HCC). However, the data remain limited, particularly in Western populations, and are often contradictory. In this study, the prognostic value of positive SOX9 immunohistochemistry was compared with that of more established markers EpCAM and K19 in a large cohort (n=216) of North American patients. The independent HCC cohort in The Cancer Gene Atlas (n=360) was utilized to validate our findings. Finally, molecular signatures associated with SOX9 -high HCC were determined. We found that the expression of SOX9, but not EpCAM or K19, was associated with worse overall survival and disease-free survival (DFS) and was an independent prognostic factor for DFS in our North American cohort, in which hepatitis C infection was the most common underlying etiology. High SOX9 mRNA level, but not increased expression of EpCAM mRNA or K19 mRNA, was also associated with worse DFS and was an independent prognostic factor for DFS in The Cancer Gene Atlas cohort. This group had underlying causes, including an increased incidence of hepatitis B, significantly different from our initial cohort. High SOX9 mRNA level is associated with molecular pathways important in HCC pathogenesis. Increased SOX9 expression is clinically and biologically relevant for HCC arising in patients with a variety of underlying etiologies. Immunohistochemistry for SOX9 is a reliable proxy for increased SOX9 mRNA and can be used to predict prognosis in HCC cases.
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- 2022
10. Liver‐Specific Deletion of Mouse Tm6sf2 Promotes Steatosis, Fibrosis, and Hepatocellular Cancer
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Elizabeth M. Brunt, Yan Xie, Julian L. Griffin, James A.J. Fitzpatrick, Peter O. Bayguinov, Zoe Hall, Elizabeth A. Molitor, Nicholas O. Davidson, Elizabeth P. Newberry, and Gregory W. Strout
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Liver Cirrhosis ,0301 basic medicine ,medicine.medical_specialty ,Very low-density lipoprotein ,Carcinoma, Hepatocellular ,Apolipoprotein B ,Lipoproteins, VLDL ,Microsomal triglyceride transfer protein ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,Internal medicine ,medicine ,Animals ,Triglycerides ,Mice, Knockout ,Hepatology ,biology ,Triglyceride ,business.industry ,Liver Neoplasms ,Membrane Proteins ,medicine.disease ,Fatty Liver ,030104 developmental biology ,Endocrinology ,Liver ,chemistry ,Lipidomics ,Knockout mouse ,biology.protein ,030211 gastroenterology & hepatology ,Steatosis ,business ,TM6SF2 - Abstract
Background and aims Human transmembrane 6 superfamily 2 (TM6SF2) variant rs58542926 is associated with NAFLD and HCC. However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased very low density lipoprotein (VLDL) secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver-specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD. Approach and results Two independent lines of Tm6 LKO mice exhibited spontaneous hepatic steatosis. Targeted lipidomic analyses showed increased triglyceride species whose distribution and abundance phenocopied findings in mice with liver-specific deletion of microsomal triglyceride transfer protein. The VLDL triglyceride secretion was reduced with small, underlipidated particles and unchanged or increased apolipoprotein B. Liver-specific adeno-associated viral, serotype 8 (AAV8) rescue using either wild-type or mutant E167K-Tm6 reduced hepatic steatosis and improved VLDL secretion. The Tm6 LKO mice fed a high milk-fat diet for 3 weeks exhibited increased steatosis and fibrosis, and those phenotypes were further exacerbated when mice were fed fibrogenic, high fat/fructose diets for 20 weeks. In two models of HCC, either neonatal mice injected with streptozotocin (NASH/STAM) and high-fat fed or with diethylnitrosamine injection plus fibrogenic diet feeding, Tm6 LKO mice exhibited increased steatosis, greater tumor burden, and increased tumor area versus Tm6 flox controls. Additionally, diethylnitrosamine-injected and fibrogenic diet-fed Tm6 LKO mice administered wild-type Tm6 or E167K-mutant Tm6 AAV8 revealed significant tumor attenuation, with tumor burden inversely correlated with Tm6 protein levels. Conclusions Liver-specific Tm6sf2 deletion impairs VLDL secretion, promoting hepatic steatosis, fibrosis, and accelerated development of HCC, which was mitigated with AAV8- mediated rescue.
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- 2021
11. Improved pathology reporting in NAFLD/NASH for clinical trials
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Kenneth A Fleming, Marc H Goldinger, Kurt Zatloukal, Robert D. Goldin, Darren Treanor, Clare McGenity, Elizabeth M. Brunt, Jonathan R. Dillman, Caitlin Rose Langford, Helmut Denk, and Daniela S. Allende
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safety ,Research Report ,medicine.medical_specialty ,Cirrhosis ,liver diseases ,liver ,Chronic liver disease ,Gastroenterology ,Pathology and Forensic Medicine ,Viewpoint ,Non-alcoholic Fatty Liver Disease ,1108 Medical Microbiology ,Internal medicine ,Pathology ,medicine ,Humans ,media_common.cataloged_instance ,European union ,FATTY LIVER-DISEASE ,media_common ,Clinical Trials as Topic ,Science & Technology ,PLACEBO ,medicine.diagnostic_test ,business.industry ,Fatty liver ,nutritional and metabolic diseases ,CHRONIC HEPATITIS ,1103 Clinical Sciences ,General Medicine ,Hepatitis C ,medicine.disease ,CANCER ,digestive system diseases ,Transplantation ,SIZE ,gastrointestinal diseases ,Liver biopsy ,BIOPSY ,Steatohepatitis ,business ,Life Sciences & Biomedicine - Abstract
Non-alcoholic fatty liver disease (NAFLD), a disorder characterised by pathological accumulation of non-visible free fatty acids and visible triglyceride in hepatocytes, is on the rise globally in both adult and paediatric populations.1 Evidence suggests that 20%–50% of the European Union and US populations exhibit features of NAFLD,2 driven by higher rates of obesity, insulin resistance and type 2 diabetes, and metabolic syndrome.3 Additionally, recognition of a growing number of patients with ‘lean NAFLD’ who are not obese, but have high levels of visceral fat, diets high in fats and carbohydrates, or who have genetic risk factors, has increased.4 Of patients with NAFLD, 6%–55% will have histological signs of non-alcoholic steatohepatitis (NASH), which if left unmanaged can lead to cirrhosis and potentially hepatocellular carcinoma.5 NAFLD has surpassed viral hepatitis as the leading cause of chronic liver disease worldwide.6 Estimates suggest that by 2030 NAFLD will overtake hepatitis C as the primary cause of liver failure requiring transplantation and that the number of NAFLD-related deaths will increase by 178%.7 Annual spending related to NAFLD care is estimated to rise exponentially from $103 billion to $1.005 trillion in the USA and from €35 billion to €334 billion in Europe between 2016 and 2025.8 While bariatric surgery and/or weight loss can be effective, they present their own challenges in delivery. There are presently no approved drugs on the market; hence, the number of clinical trials has grown by approximately 60% over the last 10 years. As both the Food and Drug Administration and the European Medicines Agency require liver biopsy for clinical trials as the ‘gold standard’, diagnosis and monitoring rely on pathological assessment of a liver biopsy.9–11 Most trials focus only on the numerically reported values of the semiquantitative assessment of four cardinal features of NAFLD/NASH—steatosis, inflammation, hepatocellular ballooning …
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- 2021
12. NAFLD: Reporting Histologic Findings in Clinical Practice
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Elizabeth M. Brunt, Danielle Carpenter, Arun J. Sanyal, Mary E. Rinella, Brent A. Neuschwander-Tetri, Rohit Loomba, Zobair M. Younossi, David E. Kleiner, and Stephen A. Harrison
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0301 basic medicine ,medicine.medical_specialty ,Cirrhosis ,Biopsy ,Disease ,digestive system ,Diagnosis, Differential ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Humans ,Hepatology ,medicine.diagnostic_test ,Hepatitis, Alcoholic ,business.industry ,Fatty liver ,nutritional and metabolic diseases ,medicine.disease ,digestive system diseases ,Clinical trial ,030104 developmental biology ,Liver ,Liver biopsy ,030211 gastroenterology & hepatology ,Steatohepatitis ,business - Abstract
The role of liver biopsy in nonalcoholic steatohepatitis (NASH) has evolved along with the increased recognition of the significance of this disease, and the unmet medical need it presents. Drug development and clinical trials are rapidly growing, as are non-invasive tests for markers of steatosis, inflammation, injury and fibrosis. Liver biopsy evaluation remains necessary for both drug development and clinical trials as the most specific means of diagnosis and patient identification for appropriate intervention. This White Paper, sponsored by the American Association for the Study of Liver Disease NASH Task Force, is a focused review of liver biopsy evaluation in fatty liver disease in subjects with presumed NAFLD for practicing clinical hepatologists and pathologists. The goal is to provide succinct and specific means for reporting the histopathologic elements of NASH, distinguishing NASH from nonalcoholic fatty liver without steatohepatitis (NAFL), and from alcoholic steatohepatitis when possible. The discussion includes the special situations of NASH in advanced fibrosisor cirrhosis, and in the pediatric population. Finally, there is discussion of semiquantitative methods of evaluation of lesions of "disease activity" and fibrosis. Tables are present for scoring and a suggested model for final reporting. Figures presented highlight the histopathologic elements of NASH.
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- 2021
13. Fifty years of impact on liver pathology
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Francesco Callea, Helmut Denk, Alastair D. Burt, Dina Tiniakos, Valeer Desmet, Eve A. Roberts, Ian R. Wanless, Andrew D. Clouston, Zachary Goodman, Stefan G. Hubscher, Annette S. H. Gouw, Michael Torbenson, Peter Schirmacher, Luigi Terracciano, David E. Kleiner, Pierre Bedossa, Hans Peter Dienes, Elizabeth M. Brunt, and Groningen Institute for Organ Transplantation (GIOT)
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Societies, Scientific ,0301 basic medicine ,History ,History, 21st Century ,Pathology and Forensic Medicine ,Organizational ,03 medical and health sciences ,0302 clinical medicine ,Models ,Pathology ,Humans ,Road map ,Cooperative Behavior ,Molecular Biology ,Pathology, Clinical/history ,Societies, Medical ,Medical education ,Societies, Medical/history ,Pathology, Clinical ,Liver Diseases ,Scientific/history ,Cell Biology ,General Medicine ,Liver Diseases/history ,History, 20th Century ,Societies, Scientific/history ,21st Century ,Scientific group ,20th Century ,Clinical/history ,030104 developmental biology ,Liver ,Order (business) ,030220 oncology & carcinogenesis ,Models, Organizational ,Original Article ,Professional association ,Liver/pathology ,Medical/history ,Psychology ,Societies ,Liver pathology ,Model - Abstract
Professional societies play a major role in medicine and science. The societies tend to be large with well-developed administrative structures. An additional model, however, is based on small groups of experts who meet regularly in an egalitarian model in order to discuss disease-specific scientific and medical problems. In order to illustrate the effectiveness of this model, the history and practices are examined of a long-standing successful example, the International Liver Pathology Group, better known as the Gnomes. The history shows that groups such as the Gnomes offer a number of important benefits not available in larger societies and nurturing such groups advances science and medicine in meaningful ways. The success of the Gnomes’ approach provides a road map for future small scientific groups. Electronic supplementary material The online version of this article (10.1007/s00428-020-02879-5) contains supplementary material, which is available to authorized users.
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- 2021
14. Biliary Adenofibroma with Invasive Carcinoma: Case Report and Review of the Literature
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Anjali Godambe, Elizabeth M. Brunt, Keith H. Fulling, and Taher Reza Kermanshahi
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Pathology ,RB1-214 - Abstract
We report a case of biliary adenofibroma with an invasive carcinoma in a 71-year-old female who presented with bilateral upper abdominal pain. Imaging revealed a 6.3 cm heterogeneously enhancing mass in the left lateral segment of the liver. Histologically, the adenofibroma showed the characteristic components as previously described of biliary adenofibromata, namely, cystic and tubular structures lined by cuboidal to low columnar biliary type epithelium and a dense fibrous stroma composed of spindled cells. Intimately admixed with the adenofibroma was a distinct tumor composed of malignant clear cells which demonstrated stromal and vascular invasion. Although mitotic figures were inconspicuous, Ki67 was brisk and p53 demonstrated 25–50% positivity. Sections also showed a von Meyenberg complex located adjacent to the tumor. This case expands the understanding of this rare tumor and proves two important assertions from previous case reports. First, the presence of an associated von Meyenberg complex with similar morphology and immunohistochemical staining pattern suggests that biliary adenofibromata and von Meyenberg complexes may share related histogenesis. Second, biliary adenofibromata harbor malignant potential and may show malignant transformation. Furthermore, this case highlights the need for these rare tumors to be followed aggressively, as their biological behavior is poorly understood.
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- 2016
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15. Banff consensus recommendations for steatosis assessment in donor livers
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Desley Neil, A. Jake Demetris, Stefan G. Hubscher, Elizabeth M. Brunt, Marta I. Minervini, and Maxwell L. Smith
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medicine.medical_specialty ,Consensus ,Hepatology ,medicine.diagnostic_test ,business.industry ,Biopsy ,Urology ,Magnification ,Consensus criteria ,medicine.disease ,Tissue Donors ,Liver Transplantation ,Transplantation ,Fatty Liver ,Increased risk ,Liver ,medicine ,Living Donors ,Humans ,Steatosis ,Living donor liver transplantation ,business ,Droplet size - Abstract
No consensus criteria or approach exist regarding assessment of steatosis in the setting of human donor liver suitability for transplantation. The Banff Working Group on Liver Allograft Pathology undertook a study to determine the consistency with which steatosis is assessed and reported in frozen sections of potential donor livers. A panel of 59 pathologists from 16 countries completed a questionnaire covering criteria used to assess steatosis in donor liver biopsies, including droplet size and magnification used; subsequently, steatosis severity was assessed in 18 whole slide images of donor liver frozen sections (n=59). Survey results (from 56/59) indicated a wide variation in definitions and approaches used to assess and report steatosis. Whole slide image assessment led to a broad range in the scores. Findings were discussed at a workshop held at the 15th Banff Conference on Allograft Pathology, September 2019. The aims of discussions were to (i) establish consensus criteria for defining "large droplet fat" (LDF) that predisposes to increased risk of initial poor graft function; and (ii) develop an algorithmic approach to determine fat droplet size, and the percentage of hepatocytes involved. Large droplet fat was defined as typically a single fat droplet that expands the involved hepatocyte and is larger than adjacent non-steatotic hepatocytes. Estimating severity of steatosis involves (i) low magnification estimate of the approximate surface area of the biopsy occupied by fat, (ii) higher magnification determination of the percentage of hepatocytes within the fatty area with large droplet fat and (iii) final score calculation. The proposed guidelines herein are intended to improve standardization in steatosis assessment of donor liver biopsies. The calculated percent LDF should be provided to the surgeon.
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- 2021
16. Complexity of ballooned hepatocyte feature recognition: Defining a training atlas for artificial intelligence-based imaging in NAFLD
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Elizabeth M. Brunt, Andrew D. Clouston, Zachary Goodman, Cynthia Guy, David E. Kleiner, Carolin Lackner, Dina G. Tiniakos, Aileen Wee, Matthew Yeh, Wei Qiang Leow, Elaine Chng, Yayun Ren, George Goh Boon Bee, Elizabeth E. Powell, Mary Rinella, Arun J. Sanyal, Brent Neuschwander-Tetri, Zobair Younossi, Michael Charlton, Vlad Ratziu, Stephen A. Harrison, Dean Tai, and Quentin M. Anstee
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Hepatology ,Liver ,Artificial Intelligence ,Non-alcoholic Fatty Liver Disease ,Biopsy ,Hepatocytes ,Humans - Abstract
Histologically assessed hepatocyte ballooning is a key feature discriminating non-alcoholic steatohepatitis (NASH) from steatosis (NAFL). Reliable identification underpins patient inclusion in clinical trials and serves as a key regulatory-approved surrogate endpoint for drug efficacy. High inter/intra-observer variation in ballooning measured using the NASH CRN semi-quantitative score has been reported yet no actionable solutions have been proposed.A focused evaluation of hepatocyte ballooning recognition was conducted. Digitized slides were evaluated by 9 internationally recognized expert liver pathologists on 2 separate occasions: each pathologist independently marked every ballooned hepatocyte and later provided an overall non-NASH NAFL/NASH assessment. Interobserver variation was assessed and a 'concordance atlas' of ballooned hepatocytes generated to train second harmonic generation/two-photon excitation fluorescence imaging-based artificial intelligence (AI).The Fleiss kappa statistic for overall interobserver agreement for presence/absence of ballooning was 0.197 (95% CI 0.094-0.300), rising to 0.362 (0.258-0.465) with a ≥5-cell threshold. However, the intraclass correlation coefficient for consistency was higher (0.718 [0.511-0.900]), indicating 'moderate' agreement on ballooning burden. 133 ballooned cells were identified using a ≥5/9 majority to train AI ballooning detection (AI-pathologist pairwise concordance 19-42%, comparable to inter-pathologist pairwise concordance of between 8-75%). AI quantified change in ballooned cell burden in response to therapy in a separate slide set.The substantial divergence in hepatocyte ballooning identified amongst expert hepatopathologists suggests that ballooning is a spectrum, too subjective for its presence or complete absence to be unequivocally determined as a trial endpoint. A concordance atlas may be used to train AI assistive technologies to reproducibly quantify ballooned hepatocytes that standardize assessment of therapeutic efficacy. This atlas serves as a reference standard for ongoing work to refine how ballooning is classified by both pathologists and AI.For the first time, we show that, even amongst expert hepatopathologists, there is poor agreement regarding the number of ballooned hepatocytes seen on the same digitized histology images. This has important implications as the presence of ballooning is needed to establish the diagnosis of non-alcoholic steatohepatitis (NASH), and its unequivocal absence is one of the key requirements to show 'NASH resolution' to support drug efficacy in clinical trials. Artificial intelligence-based approaches may provide a more reliable way to assess the range of injury recorded as "hepatocyte ballooning".
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- 2021
17. Current considerations for clinical management and care of non-alcoholic fatty liver disease: Insights from the 1st International Workshop of the Canadian NASH Network (CanNASH)
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Keyur Patel, Brent A. Neuschwander-Tetri, James Stone, Elizabeth M. Brunt, Mark G. Swain, Jean-Marie Ekoé, Stéphanie Chevalier, Massimo Pinzani, Vlad Ratziu, Quentin M. Anstee, Jordan J, Naglaa H. Shoukry, Annalisa Berzigotti, An Tang, Peter Metrakos, Alnoor Ramji, Salvatore Petta, Peter Ghali, Jeremy F. L. Cobbold, Giada Sebastiani, Harpreet S. Bajaj, Heather Watson, and Karen Seto
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medicine.medical_specialty ,business.industry ,Public health ,Fatty liver ,nutritional and metabolic diseases ,610 Medicine & health ,Non alcoholic ,General Medicine ,Disease ,medicine.disease ,digestive system ,Gastroenterology ,digestive system diseases ,Internal medicine ,Diabetes mellitus ,Epidemiology ,medicine ,Steatohepatitis ,Steatosis ,business - Abstract
Non-alcoholic fatty liver disease (NAFLD) affects approximately 8 million Canadians. NAFLD refers to a disease spectrum ranging from bland steatosis to non-alcoholic steatohepatitis (NASH). Nearly 25% of patients with NAFLD develop NASH, which can progress to liver cirrhosis and related end-stage complications. Type 2 diabetes and obesity represent the main risk factors for the disease. The Canadian NASH Network is a national collaborative organization of health care professionals and researchers with a primary interest in enhancing understanding, care, education, and research around NAFLD, with a vision of best practices for this disease state. At the 1st International Workshop of the CanNASH network in April 2021, a joint event with the single topic conference of the Canadian Association for the Study of the Liver (CASL), clinicians, epidemiologists, basic scientists, and community members came together to share their work under the theme of NASH. This symposium also marked the initiation of collaborations between Canadian and other key opinion leaders in the field representative of international liver associations. The main objective is to develop a policy framework that outlines specific targets, suggested activities, and evidence-based best practices to guide provincial, territorial, and federal organizations in developing multidisciplinary models of care and strategies to address this epidemic.
- Published
- 2021
18. Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis
- Author
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Elizabeth M. Brunt, Yan Xie, Nicholas O. Davidson, Saeed Soleyman-Jahi, Elizabeth P. Newberry, Samuel Ballentine, and Elizabeth A. Molitor
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Male ,antioxidant ,microsomal triglyceride transfer protein ,medicine.disease_cause ,Biochemistry ,Microsomal triglyceride transfer protein ,Mice ,Endocrinology ,Methionine ,Fibrosis ,Non-alcoholic Fatty Liver Disease ,Nonalcoholic fatty liver disease ,Chylomicrons ,apolipoprotein B ,oxidative stress ,NF-κB, nuclear factor kappa B ,Mice, Knockout ,biology ,TG, triglyceride ,Chemistry ,Choline Deficiency ,Intestines ,Chylomicron assembly ,Lipogenesis ,JNK, c-Jun N-terminal kinase ,MCD, methionine/choline-deficient diet ,TBARS, thiobarbituric acid reactive substance ,Female ,medicine.symptom ,NASH, nonalcoholic steatohepatitis ,TAM, tamoxifen ,Research Article ,medicine.medical_specialty ,lipid absorption ,Inflammation ,Mice, Transgenic ,Cer, ceramide ,QD415-436 ,DNL, de novo lipogenesis ,Mttp-IKO, microsomal triglyceride transfer protein knockout mice ,Internal medicine ,ALT, alanine aminotransferase ,medicine ,Animals ,intestine ,intestinal permeability ,hepatic lipogenesis ,fibrosis ,Cell Biology ,medicine.disease ,SCD, steroyl CoA desaturase ,Diet ,Fatty Liver ,lipoproteins ,HFFC, high-fat, high-fructose, high-cholesterol diet ,QC, quality control ,biology.protein ,NAFLD, nonalcoholic fatty liver disease ,Steatosis ,Oxidative stress - Abstract
Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here, we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride (TG) transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline-deficient (MCD) diet exhibited reduced hepatic TGs, inflammation, and fibrosis, associated with reduced oxidative stress and downstream activation of c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. However, when Mttpflox mice were fed an MCD for 5 weeks and then administered tamoxifen to induce Mttp-IKO, hepatic TG was reduced, but inflammation and fibrosis were increased after 10 days of reversal along with adaptive changes in hepatic lipogenic mRNAs. Extending the reversal time, following 5 weeks of MCD feeding to 30 days led to sustained reductions in hepatic TG, but neither inflammation nor fibrosis was decreased, and both intestinal permeability and hepatic lipogenesis were increased. In a second model, similar reductions in hepatic TG were observed when mice were fed a high-fat/high-fructose/high-cholesterol (HFFC) diet for 10 weeks, then switched to chow ± tamoxifen (HFFC → chow) or (HFFC → Mttp-IKO chow), but again neither inflammation nor fibrosis was affected. In conclusion, we found that blocking chylomicron assembly attenuates MCD-induced NAFLD progression by reducing steatosis, oxidative stress, and inflammation. In contrast, blocking chylomicron assembly in the setting of established hepatic steatosis and fibrosis caused increased intestinal permeability and compensatory shifts in hepatic lipogenesis that mitigate resolution of inflammation and fibrogenic signaling despite 50–90-fold reductions in hepatic TG.
- Published
- 2021
19. Liver biopsy reliability in clinical trials: Thoughts from a liver pathologist
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Elizabeth M. Brunt
- Subjects
Clinical trial ,medicine.medical_specialty ,Hepatology ,medicine.diagnostic_test ,business.industry ,Liver biopsy ,medicine ,MEDLINE ,Radiology ,business ,Reliability (statistics) - Published
- 2020
20. Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials
- Author
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Elizabeth M. Brunt, Laura A. Wilson, Arun J. Sanyal, David E. Kleiner, and Brent A. Neuschwander-Tetri
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cirrhosis ,Hepatology ,medicine.diagnostic_test ,business.industry ,Obeticholic acid ,Odds ratio ,medicine.disease ,Placebo ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Fibrosis ,Internal medicine ,Biopsy ,Nonalcoholic fatty liver disease ,medicine ,030211 gastroenterology & hepatology ,Steatohepatitis ,business - Abstract
Hepatocellular injury and inflammation are believed to be the primary drivers of fibrogenesis that ultimately lead to cirrhosis in patients with nonalcoholic steatohepatitis (NASH). This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease activity score (NAS) ≥2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. The primary outcome for the study was fibrosis improvement from baseline to end of treatment, defined as a 1-point or more improvement in fibrosis stage. This is a retrospective analysis of biopsy data collected from the NASH Clinical Research Network Pathology Committee of Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (FLINT) baseline and final biopsies. Treatment group-adjusted univariable and multivariable logistic regression models related improvement in fibrosis to improvements in other histologic variables, resolution of steatohepatitis, and improvement in the NAS ≥2. In PIVENS 221 subjects had baseline and 96-week biopsies, and in FLINT 200 subjects had baseline and 72-week biopsies. Improvement in fibrosis was found in 38% of PIVENS and 29% of FLINT biopsies; fibrosis improvement was more likely in treated than placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS, odds ratio [OR], 3.9; 95% confidence interval [CI] 2.0-7.6; P < 0.001; FLINT, OR, 8.0; 95% CI 3.1-20.9; P < 0.001), and improved NAS by ≥2 (PIVENS, OR, 2.4; 95% CI 1.3-4.3; P = 0.003; FLINT, OR, 4.2; 95% CI 2.1-8.3; P < 0.001). Improvement in histologic features associated with improved fibrosis for both studies included steatosis, ballooning, Mallory-Denk bodies, and portal, but not lobular, inflammation. Conclusion: These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.
- Published
- 2019
21. Tu1273: BLOCKING CHYLOMICRON ASSEMBLY PROMOTES HEPATIC TUMORIGENESES BY ALTERING BILE ACID AND OXYSTEROL METABOLISM AND IMPAIRING INTESTINAL BARRIER FUNCTION
- Author
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Yan Xie, Valerie Blanc, Elizabeth A. Molitor, Elizabeth M. Brunt, Elizabeth P. Newberry, and Nicholas O. Davidson
- Subjects
Hepatology ,Gastroenterology - Published
- 2022
22. Hepatocellular adenomas: the expanding epidemiology
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Paulette Bioulac-Sage, Elizabeth M. Brunt, and Christine Sempoux
- Subjects
medicine.medical_specialty ,Histology ,Carcinoma, Hepatocellular ,business.industry ,Liver Neoplasms ,MEDLINE ,General Medicine ,Bioinformatics ,Pathology and Forensic Medicine ,Adenoma, Liver Cell ,Text mining ,Epidemiology ,Medicine ,Humans ,business - Published
- 2021
23. From NAFLD to MAFLD: Implications of a Premature Change in Terminology
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Rohit Loomba, Arun J. Sanyal, Zachary Goodman, Zobair M. Younossi, Elizabeth M. Brunt, David E. Cohen, Mary E. Rinella, and Stephen A. Harrison
- Subjects
0301 basic medicine ,Biomedical Research ,media_common.quotation_subject ,Context (language use) ,Disease ,Patient advocacy ,Terminology ,law.invention ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Drug Development ,law ,Non-alcoholic Fatty Liver Disease ,Terminology as Topic ,medicine ,Humans ,media_common ,Hepatology ,business.industry ,Ambiguity ,Public relations ,Root cause ,medicine.disease ,030104 developmental biology ,CLARITY ,030211 gastroenterology & hepatology ,business ,Psychology ,Biomarkers - Abstract
Despite the substantial gains in our understanding of NAFLD/NASH over the past 2 decades, there has been some dissatisfaction with the terminology "non-alcoholic" which overemphasizes "alcohol" and underemphasizes the root cause of this liver disease, namely, the predisposing metabolic risk factors. As a potential remedy, a name change from NAFLD to metabolic associated fatty liver disease (MAFLD) has been proposed. Although MAFLD reflects the relevant risk factors for this liver disease, this term is still suboptimal, leaving a great deal of ambiguity. Here, we caution that changing the name without understanding its broad implications can have a negative impact on the field. In this context, changing the terminology without new understanding of the molecular basis of the disease entity, new insights in risk stratification or other important aspect of this liver disease, can create unnecessary confusion which could negatively impact the field. At a time when the field is facing substantial challenges around disease awareness as well as clarity of acceptable endpoints for drug development and biomarker discovery, changing the terminology from one suboptimal name to another suboptimal name without full assessment is expected to deepen these challenges. In the context of this debate about terminology, we recommend the creation of a true international consensus group to include all the relevant scientific liver societies (AASLD, EASL, ALEH, APASL), patient advocacy organizations, bio-pharmaceutical industry, regulatory agencies and policy makers. A consensus meeting must assess the impact and consequences of changing the terminology based on the available evidence and make recommendations that will move the field forward. By this approach, a true collaborative international and inclusive consensus can be adopted by all stakeholders dealing with this important global liver disease.
- Published
- 2020
24. Deep learning quantification of percent steatosis in donor liver biopsy frozen sections
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Matthew K. Matlock, S. Joshua Swamidass, Lulu Sun, Ling Chen, Jon N. Marsh, Joseph P. Gaut, Elizabeth M. Brunt, and Ta-Chiang Liu
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Steatosis ,Intraclass correlation ,medicine.medical_treatment ,Biopsy ,H&E stain ,lcsh:Medicine ,Convolutional neural network ,Liver transplantation ,Severity of Illness Index ,General Biochemistry, Genetics and Molecular Biology ,Image analysis ,03 medical and health sciences ,0302 clinical medicine ,Deep Learning ,Image Processing, Computer-Assisted ,Living Donors ,Medicine ,Frozen Sections ,Humans ,lcsh:R5-920 ,Frozen section procedure ,medicine.diagnostic_test ,business.industry ,Deep learning ,lcsh:R ,Digital pathology ,Molecular Sequence Annotation ,General Medicine ,medicine.disease ,Immunohistochemistry ,Liver Transplantation ,Fatty Liver ,030104 developmental biology ,030220 oncology & carcinogenesis ,Radiology ,Artificial intelligence ,Neural Networks, Computer ,lcsh:Medicine (General) ,business ,Algorithms - Abstract
Background Pathologist evaluation of donor liver biopsies provides information for accepting or discarding potential donor livers. Due to the urgent nature of the decision process, this is regularly performed using frozen sectioning at the time of biopsy. The percent steatosis in a donor liver biopsy correlates with transplant outcome, however there is significant inter- and intra-observer variability in quantifying steatosis, compounded by frozen section artifact. We hypothesized that a deep learning model could identify and quantify steatosis in donor liver biopsies. Methods We developed a deep learning convolutional neural network that generates a steatosis probability map from an input whole slide image (WSI) of a hematoxylin and eosin-stained frozen section, and subsequently calculates the percent steatosis. Ninety-six WSI of frozen donor liver sections from our transplant pathology service were annotated for steatosis and used to train (n = 30 WSI) and test (n = 66 WSI) the deep learning model. Findings The model had good correlation and agreement with the annotation in both the training set (r of 0.88, intraclass correlation coefficient [ICC] of 0.88) and novel input test sets (r = 0.85 and ICC=0.85). These measurements were superior to the estimates of the on-service pathologist at the time of initial evaluation (r = 0.52 and ICC=0.52 for the training set, and r = 0.74 and ICC=0.72 for the test set). Interpretation Use of this deep learning algorithm could be incorporated into routine pathology workflows for fast, accurate, and reproducible donor liver evaluation. Funding Mid-America Transplant Society
- Published
- 2020
25. Systemic Therapy for Combined Hepatocellular-Cholangiocarcinoma: A Single-Institution Experience
- Author
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Amy Zhou, Manik Amin, William C. Chapman, Benjamin R. Tan, Jesse Keller, Ashley Morton, Kathryn J. Fowler, Maria B. Doyle, Elizabeth M. Brunt, Neeta Vachharajani, and Nikolaos A. Trikalinos
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Organoplatinum Compounds ,medicine.medical_treatment ,Deoxycytidine ,Cholangiocarcinoma ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,Hepatectomy ,Humans ,Medicine ,Progression-free survival ,Response Evaluation Criteria in Solid Tumors ,Aged ,Retrospective Studies ,Aged, 80 and over ,Chemotherapy ,business.industry ,Liver Neoplasms ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Gemcitabine ,Neoadjuvant Therapy ,Progression-Free Survival ,Regimen ,Bile Duct Neoplasms ,Liver ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,030211 gastroenterology & hepatology ,Bile Ducts ,business ,medicine.drug - Abstract
Background: Combined hepatocellular-cholangiocarcinoma tumors (cHCC-CCA) are a heterogeneous group of rare malignancies that have no established optimal treatment. Patients and Methods: We identified patients with cHCC-CCA treated at a tertiary center and retrospectively examined their histology, interventions, and outcomes. We calculated disease control rate (DCR), disease progression, overall survival, and progression-free survival (PFS) between treatment subgroups. Results: A total of 123 patients were evaluable. Interventions included resection, locoregional therapy, transplant, chemotherapy, and targeted agents. Ultimately, 68 patients received systemic treatment-57 with gemcitabine plus either 5-fluoropyrimidine (5-FU) or a platinum combination. Disease progression was more common in the gemcitabine/5-FU group versus gemcitabine/platinum (P=.028), whereas DCR favored gemcitabine/platinum (78.4% vs 38.5%; P=.0143). Median PFS from time of initial diagnosis favored the gemcitabine/platinum group, but the difference did not reach statistical significance. Targeted agents had minimal to no effect on survival metrics. Conclusions: Gemcitabine/platinum seems to be a superior regimen for patients with cHCC-CCA who require systemic treatment. Further studies are needed to clarify the regimen's efficacy and applicability in patient subgroups.
- Published
- 2018
26. cHCC-CCA
- Author
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Rebecca A. Miksad, Fukuo Kondo, Young Nyun Park, Yasuni Nakanuma, Zachary Goodman, Irene Ng, Gregory J. Gores, Elizabeth M. Brunt, Shinichi Aishima, Christine Sempoux, Masayuki Nakano, Wilson M. S. Tsui, Massimo Roncalli, Matthew M. Yeh, David S. Klimstra, Romil Saxena, Hirohisa Yano, Michiie Sakamoto, Mina Komuta, Alberto Quaglia, Kathryn J. Fowler, Jessica Zucman-Rossi, Yoh Zen, Neil D. Theise, Valérie Paradis, Alex Kagen, Xin Wei Wang, Aileen Wee, Annette S. H. Gouw, Claude B. Sirlin, Tania Roskams, Pierre-Alain Clavien, Ashley Stueck, Swan N. Thung, Groningen Institute for Organ Transplantation (GIOT), UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, and UCL - (SLuc) Service d'anatomie pathologique
- Subjects
Enhanced ct ,IMAGING FEATURES ,KERATIN 19 ,Computed tomography ,Medical Biochemistry and Metabolomics ,Terminology ,Cholangiocarcinoma ,CLINICOPATHOLOGICAL SIGNIFICANCE ,0302 clinical medicine ,Cholangiolocellular Carcinoma ,Cancer ,medicine.diagnostic_test ,Liver Disease ,Philosophy ,Liver Neoplasms ,Liver ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Outcome data ,Life Sciences & Biomedicine ,Liver pathology ,Liver Cancer ,Carcinoma, Hepatocellular ,Clinical Sciences ,Immunology ,CYTOKERATIN-19 EXPRESSION ,Article ,03 medical and health sciences ,Rare Diseases ,CHOLANGIOLOCELLULAR CARCINOMA ,Terminology as Topic ,medicine ,Humans ,Effective treatment ,INTRAHEPATIC CHOLANGIOCARCINOMA ,COMPUTED-TOMOGRAPHY ,PROGENITOR-CELL ORIGIN ,Religious studies ,Aged ,Science & Technology ,Gastroenterology & Hepatology ,Hepatology ,Carcinoma ,Hepatocellular ,COMBINED HEPATOCELLULAR-CHOLANGIOCARCINOMA ,Radiography ,Digestive Diseases ,ENHANCED CT - Abstract
Author(s): Brunt, Elizabeth; Aishima, Shinichi; Clavien, Pierre-Alain; Fowler, Kathryn; Goodman, Zachary; Gores, Gregory; Gouw, Annette; Kagen, Alex; Klimstra, David; Komuta, Mina; Kondo, Fukuo; Miksad, Rebecca; Nakano, Masayuki; Nakanuma, Yasuni; Ng, Irene; Paradis, Valerie; Nyun Park, Young; Quaglia, Alberto; Roncalli, Massimo; Roskams, Tania; Sakamoto, Michiie; Saxena, Romil; Sempoux, Christine; Sirlin, Claude; Stueck, Ashley; Thung, Swan; Tsui, WMS; Wang, Xin-Wei; Wee, Aileen; Yano, Hirohisa; Yeh, Matthew; Zen, Yoh; Zucman-Rossi, Jessica; Theise, Neil | Abstract: Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation.ConclusionIt is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (HaE); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).
- Published
- 2018
27. Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease
- Author
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Claude B. Sirlin, Elhamy Heba, Jeffrey B. Schwimmer, James Tonascia, Joel E. Lavine, Mark L. Van Natta, Andrew T. Trout, Michael S. Middleton, Wei Shen, Prakash Masand, Edward Doo, Adina Alazraki, Elizabeth M. Brunt, Gavin Hamilton, and David E. Kleiner
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Cysteamine ,Sensitivity and Specificity ,Gastroenterology ,Article ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Humans ,Prospective Studies ,Child ,Cystine Depleting Agents ,Prospective cohort study ,Hepatology ,medicine.diagnostic_test ,business.industry ,Proton density fat fraction ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Confidence interval ,Cross-Sectional Studies ,Liver ,Liver biopsy ,Female ,030211 gastroenterology & hepatology ,Radiology ,Protons ,Steatosis ,business - Abstract
Author(s): Middleton, Michael S; Van Natta, Mark L; Heba, Elhamy R; Alazraki, Adina; Trout, Andrew T; Masand, Prakash; Brunt, Elizabeth M; Kleiner, David E; Doo, Edward; Tonascia, James; Lavine, Joel E; Shen, Wei; Hamilton, Gavin; Schwimmer, Jeffrey B; Sirlin, Claude B; NASH Clinical Research Network | Abstract: We assessed the performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in children to stratify hepatic steatosis grade before and after treatment in the Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease in Children (CyNCh) trial, using centrally scored histology as reference. Participants had multiecho 1.5 Tesla (T) or 3T MRI on scanners from three manufacturers. Of 169 enrolled children, 110 (65%) and 83 (49%) had MRI and liver biopsy at baseline and at end of treatment (EOT; 52 weeks), respectively. At baseline, 17% (19 of 110), 28% (31 of 110), and 55% (60 of 110) of liver biopsies showed grades 1, 2, and 3 histological steatosis; corresponding PDFF (meann±nSD) values were 10.9n±n4.1%, 18.4n±n6.2%, and 25.7n±n9.7%, respectively. PDFF classified grade 1 versus 2-3 and 1-2 versus 3 steatosis with areas under receiving operator characteristic curves (AUROCs) of 0.87 (95% confidence interval [CI], 0.80, 0.94) and 0.79 (0.70, 0.87), respectively. PDFF cutoffs at 90% specificity were 17.5% for grades 2-3 steatosis and 23.3% for grade 3 steatosis. At EOT, 47% (39 of 83), 41% (34 of 83), and 12% (10 of 83) of biopsies showed improved, unchanged, and worsened steatosis grade, respectively, with corresponding PDFF (meann±nSD) changes of -7.8n±n6.3%, -1.2n±n7.8%, and 4.9n±n5.0%, respectively. PDFF change classified steatosis grade improvement and worsening with AUROCs (95% CIs) of 0.76 (0.66, 0.87) and 0.83 (0.73, 0.92), respectively. PDFF change cut-off values at 90% specificity were -11.0% and +5.5% for improvement and worsening.ConclusionMRI-estimated PDFF has high diagnostic accuracy to both classify and predict histological steatosis grade and change in histological steatosis grade in children with NAFLD. (Hepatology 2018;67:858-872).
- Published
- 2018
28. Nonalcoholic fatty liver disease and the ongoing role of liver biopsy evaluation
- Author
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Elizabeth M. Brunt
- Subjects
0301 basic medicine ,Nonalcoholic steatohepatitis ,medicine.medical_specialty ,Pathology ,Hepatology ,medicine.diagnostic_test ,business.industry ,Fibrosis stage ,Review Article ,medicine.disease ,Gastroenterology ,Liver tests ,03 medical and health sciences ,Liver disease ,030104 developmental biology ,0302 clinical medicine ,Liver biopsy ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,030211 gastroenterology & hepatology ,business ,Review Articles - Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common underlying causes of chronically elevated liver tests and liver disease in adults and children worldwide and may be strongly suspected if not diagnosed by ever evolving and available serologic and imaging-based noninvasive tests. However, the definitive diagnosis of the most progressive form of NAFLD, nonalcoholic steatohepatitis, and the identification of fibrosis stage still require liver biopsy evaluation as noninvasive testing has not replaced some of the specifics or the totality of information obtainable from liver biopsy. In this review, both the role and value of a liver biopsy evaluation in NAFLD/ nonalcoholic steatohepatitis are examined from publications related to a selected variety of settings. Details of the most commonly used semiquantitative methods of analysis are discussed, and some useful potential pitfalls for differential diagnostic consideration in liver biopsy interpretation are given. (Hepatology Communications 2017;1:370-378).
- Published
- 2017
29. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis
- Author
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ILKe Nalbantoglu, Hideji Fujiwara, Christopher L. Holley, Brian N. Finck, William G. McDonald, Elizabeth M. Brunt, Wesley T. Hodges, Kyle S. McCommis, Jean E. Schaffer, and Jerry R. Colca
- Subjects
Male ,0301 basic medicine ,medicine.drug_class ,Anion Transport Proteins ,Drug Evaluation, Preclinical ,Pharmacology ,Exosomes ,Mitochondrial Membrane Transport Proteins ,Article ,Random Allocation ,03 medical and health sciences ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,Nonalcoholic fatty liver disease ,Hepatic Stellate Cells ,Animals ,Medicine ,Molecular Targeted Therapy ,Thiazolidinedione ,Mitochondrial pyruvate carrier 2 ,Hepatology ,business.industry ,Acetophenones ,medicine.disease ,Hepatic stellate cell activation ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Hepatocyte ,Hepatic stellate cell ,Thiazolidinediones ,business ,Hepatic fibrosis - Abstract
Diseases of the liver related to metabolic syndrome have emerged as the most common and undertreated hepatic ailments. The cause of nonalcoholic fatty liver disease is the aberrant accumulation of lipid in hepatocytes, though the mechanisms whereby this leads to hepatocyte dysfunction, death, and hepatic fibrosis are still unclear. Insulin-sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose-limiting side effects thought to be due to activation of the peroxisome proliferator–activated receptor γ. We sought to determine whether a next-generation thiazolidinedione with markedly diminished ability to activate peroxisome proliferator–activated receptor γ (MSDC-0602) would retain its efficacy for treating NASH in a rodent model. We also determined whether some or all of these beneficial effects would be mediated through an inhibitory interaction with the mitochondrial pyruvate carrier 2 (MPC2), which was recently identified as a mitochondrial binding site for thiazolidinediones, including MSDC-0602. We found that MSDC-0602 prevented and reversed liver fibrosis and suppressed expression of markers of stellate cell activation in livers of mice fed a diet rich in trans-fatty acids, fructose, and cholesterol. Moreover, mice with liver-specific deletion of MPC2 were protected from development of NASH on this diet. Finally, MSDC-0602 directly reduced hepatic stellate cell activation in vitro, and MSDC-0602 treatment or hepatocyte MPC2 deletion also limited stellate cell activation indirectly by affecting secretion of exosomes from hepatocytes. Conclusion: Collectively, these data demonstrate the effectiveness of MSDC-0602 for attenuating NASH in a rodent model and suggest that targeting hepatic MPC2 may be an effective strategy for pharmacologic development. (Hepatology 2017;65:1543-1556).
- Published
- 2017
30. Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease
- Author
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Elizabeth M. Brunt, Ryan M. Gill, Norah A. Terrault, Patricia Belt, Anna Mae Diehl, Brent A. Neuschwander-Tetri, Srinivasan Dasarathy, Oscar W. Cummings, Matthew M. Yeh, Cynthia Behling, Kris V. Kowdley, Cynthia D. Guy, Arun J. Sanyal, James Tonascia, Laura Wilson, David E. Kleiner, Melissa J. Contos, Rohit Loomba, Naga Chalasani, and Joel E. Lavine
- Subjects
Adult ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,Gastroenterology and Hepatology ,Weight Gain ,Gastroenterology ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Risk Factors ,Internal medicine ,Nonalcoholic fatty liver disease ,Biopsy ,medicine ,Humans ,Aspartate Aminotransferases ,Stage (cooking) ,Prospective cohort study ,030304 developmental biology ,Original Investigation ,0303 health sciences ,Academic Medical Centers ,medicine.diagnostic_test ,business.industry ,Research ,General Medicine ,Middle Aged ,medicine.disease ,digestive system diseases ,United States ,3. Good health ,Online Only ,Liver ,Disease Progression ,030211 gastroenterology & hepatology ,Female ,Steatosis ,Steatohepatitis ,Metabolic syndrome ,business ,Cohort study - Abstract
Key Points Question In patients with nonalcoholic fatty liver disease who are not undergoing specific therapeutic interventions, what factors are associated with progression and regression of hepatic fibrosis? Findings In this cohort study of 446 patients, high baseline nonalcoholic fatty liver disease activity score and changes in the score were associated with concordant changes in fibrosis. Weight gain, high baseline aspartate aminotransferase level, and increases in the aspartate aminotransferase level were associated with fibrosis progression. Meaning These data may support the use of therapeutics targeting disease activity in nonalcoholic steatohepatitis and the use of short-term changes in the nonalcoholic fatty liver disease activity score as an end point in such clinical trials; in clinical practice, weight gain and an increasing aspartate aminotransferase level should increase suspicion of increasing fibrosis., Importance The histologic evolution of the full spectrum of nonalcoholic fatty liver disease (NAFLD) and factors associated with progression or regression remain to be definitively established. Objective To evaluate the histologic evolution of NAFLD and the factors associated with changes in disease severity over time. Design, Setting, and Participants A prospective cohort substudy from the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database study, a noninterventional registry, was performed at 8 university medical research centers. Masked assessment of liver histologic specimens was performed, using a prespecified protocol to score individual biopsies. Participants included 446 adults with NAFLD enrolled in the NASH CRN Database studies between October 27, 2004, and September 13, 2013, who underwent 2 liver biopsies 1 or more year apart. Data analysis was performed from October 2016 to October 2018. Main Outcomes and Measures Progression and regression of fibrosis stage, using clinical, laboratory, and histologic findings, including the NAFLD activity score (NAS) (sum of scores for steatosis, lobular inflammation, and ballooning; range, 0-8, with 8 indicating more severe disease). Results A total of 446 adults (mean [SD] age, 47 [11] years; 294 [65.9%] women) with NAFLD (NAFL, 86 [19.3%]), borderline NASH (84 [18.8%]), and definite NASH (276 [61.9%]) were studied. Over a mean (SD) interval of 4.9 (2.8) years between biopsies, NAFL resolved in 11 patients (12.8%) and progressed to steatohepatitis in 36 patients (41.9%). Steatohepatitis resolved in 24 (28.6%) of the patients with borderline NASH and 61 (22.1%) of those with definite NASH. Fibrosis progression or regression by at least 1 stage occurred in 132 (30%) and 151 [34%] participants, respectively. Metabolic syndrome (20 [95%] vs 108 [72%]; P = .03), baseline NAS (mean [SD], 5.0 [1.4] vs 4.3 [1.6]; P = .005), and smaller reduction in NAS (−0.2 [2] vs −0.9 [2]; P, This cohort study evaluates the progression and regression of hepatic fibrosis over time in association with the severity of nonalcoholic fatty liver disease.
- Published
- 2019
31. Hepatocellular carcinoma: Where are we in 2018?
- Author
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Patrick M. Grierson, Kevin M. Korenblat, Nael Saad, Elizabeth M. Brunt, Leigh Anne Dageforde, Kathryn J. Fowler, Vijay Subramanian, Benjamin R. Tan, Maria B. Doyle, William C. Chapman, Min Xu, Adeel S. Khan, and Yiing Lin
- Subjects
Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,business.industry ,Liver Neoplasms ,MEDLINE ,General Medicine ,medicine.disease ,Hepatitis B ,Text mining ,Liver ,Hepatocellular carcinoma ,Internal medicine ,Population Surveillance ,medicine ,Carcinoma ,Humans ,Mass Screening ,Surgery ,business ,Liver pathology ,Early Detection of Cancer - Published
- 2018
32. Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice
- Author
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Stavra A. Xanthakos, Joel E. Lavine, Katherine P. Yates, Jeffrey B. Schwimmer, Jean P. Molleston, Philip Rosenthal, Karen F. Murray, Miriam B. Vos, Ajay K. Jain, Ann O. Scheimann, Tamir Miloh, Mark Fishbein, Cynthia A. Behling, Elizabeth M. Brunt, Arun J. Sanyal, James Tonascia, Stephanie Abrams, Donna Garner, Paula Hertel, Ryan Himes, Alicia Lawson, Nicole Triggs, Kristin Bramlage, April Carr, Kim Cecil, Meghan McNeill, Marialena Mouzaki, Andrew Trout, Stavra Xanthakos, Kimberlee Bernstein, Stephanie DeVore, Rohit Kohli, Kathleen Lake, Daniel Podberesky, Alex Towbin, Ali Mencin, Elena Reynoso, Adina Alazraki, Rebecca Cleeton, Maria Cordero, Albert Hernandez, Saul Karpen, Jessica Cruz Munos, Nicholas Raviele, Miriam Vos, Molly Bozic, Laura Carr, Oscar W. Cummings, Kathryn Harlow, Ann Klipsch, Emily Ragozzino, Girish Rao, Kimberly Kafka, Ann Scheimann, Mark H. Fishbein, Joy Ito, Saeed Mohammad, Peter F. Whitington, Sarah Barlow, Danielle Carpenter, Theresa Cattoor, Jose Derdoy, Janet Freebersyser, Ajay Jain, Debra King, Jinping Lai, Joan Siegner, Susan Stewart, Susan Torretta, Kristina Wriston, Jorge Angeles, Jennifer Arin, Cynthia Behling, Craig Bross, Carissa Carrier, Jennifer Collins, Diana De La Pena, Janis Durelle, Mary Catherine Huckaby, Michael S. Middleton, Kimberly Newton, Claude Sirlin, Patricia Ugalde-Nicalo, Jesse Courtier, Ryan Gill, Camille Langlois, Emily Rothbaum Perito, Patrika Tsai, Niviann Blondet, Kara Cooper, Karen Murray, Randolph Otto, Matthew Yeh, Melissa Young, Kathryn Fowler, David E. Kleiner, Edward C. Doo, Sherry Hall, Jay H. Hoofnagle, Patricia R. Robuck, Averell H. Sherker, Rebecca Torrance, Patricia Belt, Jeanne M. Clark, John Dodge, Michele Donithan, Milana Isaacson, Mariana Lazo, Jill Meinert, Laura Miriel, Emily P. Sharkey, Jacqueline Smith, Michael Smith, Alice Sternberg, Mark L. Van Natta, Annette Wagoner, Laura A. Wilson, and Goro Yamada
- Subjects
Blood Glucose ,Male ,0301 basic medicine ,Pediatric Obesity ,Time Factors ,Cirrhosis ,Biopsy ,Type 2 diabetes ,Chronic liver disease ,Severity of Illness Index ,Gastroenterology ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Risk Factors ,Nonalcoholic fatty liver disease ,Medicine ,Glucose homeostasis ,Prospective Studies ,Child ,Randomized Controlled Trials as Topic ,Fatty liver ,Age Factors ,Alanine Transaminase ,Treatment Outcome ,Disease Progression ,Female ,030211 gastroenterology & hepatology ,medicine.medical_specialty ,Adolescent ,Risk Assessment ,digestive system ,Article ,03 medical and health sciences ,Internal medicine ,Humans ,Aspartate Aminotransferases ,Healthy Lifestyle ,Hepatology ,business.industry ,nutritional and metabolic diseases ,Odds ratio ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,business ,Risk Reduction Behavior ,Body mass index ,Biomarkers - Abstract
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth. METHODS: We compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8–17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis. RESULTS: At enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH or in fibrosis occurred in 36% of the children, and both occurred in 11% of the children. Any improvement in NASH or fibrosis occurred in 52%, and both occurred in 20% of children. Type 2 diabetes developed in 5% of the cohort. Any progression to NASH and/or fibrosis was associated with adolescent age, higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein-cholesterol at baseline, increasing level of alanine aminotransferase, and hemoglobin A1C (P < .05). Progression to NASH and/or fibrosis were also associated with increasing level of gamma-glutamyl transferase and development of type 2 diabetes (P < .01). Increasing level of gamma-glutamyl transferase also associated with reduced odds of any improvement (P = .003). CONCLUSIONS: One-third of children with NAFLD enrolled in placebo groups of clinical trials had histologic features of progression within 2 years, in association with increasing obesity and serum levels of aminotransferases and loss of glucose homeostasis.
- Published
- 2020
33. Hepatic small vessel neoplasm, a rare infiltrative vascular neoplasm of uncertain malignant potential
- Author
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Linda D. Ferrell, Ta-Chiang Liu, Elizabeth M. Brunt, ILKe Nalbantoglu, Nancy M. Joseph, Celia Marginean, Swan N. Thung, Hala R. Makhlouf, Ryan M. Gill, Dale C. Snover, Cheryl Mather, Benjamin Buelow, Venancio Avancini Ferreira Alves, Christine Sempoux, and Matthew M. Yeh
- Subjects
Male ,Pathology ,DNA Mutational Analysis ,Metastasis ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Diagnosis ,80 and over ,Angiosarcoma ,2.1 Biological and endogenous factors ,Aetiology ,Cancer ,Aged, 80 and over ,Tumor ,Liver Neoplasms ,Middle Aged ,Immunohistochemistry ,GTP-Binding Protein alpha Subunits ,Vascular Neoplasms ,Liver ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Cavernous ,Hemangioma ,Adult ,medicine.medical_specialty ,Proliferative index ,Class I Phosphatidylinositol 3-Kinases ,Clinical Sciences ,Hemangiosarcoma ,Biology ,Article ,Pathology and Forensic Medicine ,Diagnosis, Differential ,Proto-Oncogene Proteins c-myc ,Young Adult ,03 medical and health sciences ,Rare Diseases ,GNAQ ,Predictive Value of Tests ,Terminology as Topic ,Biomarkers, Tumor ,medicine ,Vascular Neoplasm ,Humans ,Aged ,Cell Proliferation ,Gq-G11 ,Neoplasm Grading ,medicine.disease ,Hemangioma, Cavernous ,Ki-67 Antigen ,Hepatic small vessel neoplasm ,Differential ,Mutation ,GTP-Binding Protein alpha Subunits, Gq-G11 ,Tumor Suppressor Protein p53 ,Differential diagnosis ,Digestive Diseases ,Biomarkers - Abstract
Characteristic but rare vascular neoplasms in the adult liver composed of small vessels with an infiltrative border were collected from an international group of collaborators over a 5-year period (N = 17). These tumors were termed hepatic small vessel neoplasm (HSVN), and the histologic differential diagnosis was angiosarcoma (AS). The average age of patients was 54 years (range, 24–83 years). HSVN was more common in men. The average size was 2.1 cm (range, 0.2–5.5 cm). Diagnosis was aided by immunohistochemical stains for vascular lineage (CD31, CD34, FLI-1), which were uniformly positive in HSVN. Immunohistochemical stains (p53, c-Myc, GLUT-1, and Ki-67) for possible malignant potential are suggestive of a benign/low-grade tumor. Capture-based next-generation sequencing (using an assay that targets the coding regions of more than 500 cancer genes) identified an activating hotspot GNAQ mutation in 2 of 3 (67%) tested samples, and one of these cases also had a hotspot mutation in PIK3CA. When compared with hepatic AS (n = 10) and cavernous hemangioma (n = 6), the Ki-67 proliferative index is the most helpful tool in excluding AS, which demonstrated a tumor cell proliferative index greater than 10% in all cases. Strong p53 and diffuse c-Myc staining was also significantly associated with AS but not with HSVN or cavernous hemangioma. There have been no cases with rupture/hemorrhage, disseminated intravascular coagulation, or Kasabach-Merritt syndrome. Thus far, there has been no metastasis or recurrence of HSVN, but complete resection and close clinical follow-up are recommended because the outcome remains unknown.
- Published
- 2016
34. Imaging Features of Biphenotypic Primary Liver Carcinoma (Hepatocholangiocarcinoma) and the Potential to Mimic Hepatocellular Carcinoma: LI-RADS Analysis of CT and MRI Features in 61 Cases
- Author
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Theodora A. Potretzke, Elizabeth M. Brunt, Jay P. Heiken, Benjamin R. Tan, M.B. Majella Doyle, and Kathryn J. Fowler
- Subjects
Adult ,Male ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Contrast Media ,030218 nuclear medicine & medical imaging ,Cholangiocarcinoma ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Aged ,Liver imaging ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Liver Neoplasms ,Magnetic resonance imaging ,Mean age ,General Medicine ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Phenotype ,Primary Liver Carcinoma ,Tomography x ray computed ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Female ,Radiology ,Differential diagnosis ,Tomography, X-Ray Computed ,business - Abstract
The purpose of this study was to determine the frequency with which biphenotypic primary liver carcinoma (also called hepatocholangiocarcinoma) may be misclassified as hepatocellular carcinoma (HCC) when only Liver Imaging Reporting and Data System (LI-RADS) major features are used and after consideration of ancillary features.A review of all pathologically proven biphenotypic primary liver carcinomas diagnosed at one institution from 2006 to 2014 was performed. Two subspecialized abdominal imagers independently reviewed cases using LI-RADS version 2014 and assigned major features, ancillary features, and additional findings. The number of lesions meeting imaging criteria for HCC was determined after assessment of major features alone and after the addition of ancillary features.Sixty-one patients (30 men, 31 women; mean age, 62 years; range, 22-89 years) with biphenotypic primary liver carcinomas who underwent pretreatment multiphasic contrast-enhanced MRI (48 patients) or CT (13 patients) were included. According to LI-RADS major features alone, 33 (54.1%) lesions met criteria for HCC and therefore might have been misclassified. Thirteen had arterial phase hyperenhancement, washout, and a capsule. Twenty had arterial phase hyperenhancement with either washout (15 lesions) or a capsule (five lesions). After evaluation of ancillary features, 29 of these potential mimics exhibited at least one ancillary feature favoring non-HCC malignancy, possibly leading to appropriate reclassification. Of the four carcinomas that met criteria for HCC by major features and did not have ancillary features favoring non-HCC malignancy, two (3.3% of all tumors) fell within the Milan criteria.Most biphenotypic primary liver carcinomas have features of non-HCC malignancy and can be correctly categorized as such. Addition of ancillary features to major features may improve diagnostic accuracy over systems in which only major features are used.
- Published
- 2016
35. Acidophil bodies in nonalcoholic steatohepatitis
- Author
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Matthew M. Yeh, Linda D. Ferrell, Laura A. Wilson, Kris V. Kowdley, Patricia Belt, and Elizabeth M. Brunt
- Subjects
Adult ,Liver Cirrhosis ,Male ,0301 basic medicine ,Nonalcoholic steatohepatitis ,Pathology ,medicine.medical_specialty ,Adolescent ,Databases, Factual ,Apoptosis ,Severity of Illness Index ,digestive system ,Article ,Pathology and Forensic Medicine ,Extracellular Vesicles ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Predictive Value of Tests ,Biopsy ,Nonalcoholic fatty liver disease ,medicine ,Humans ,Child ,Cell Size ,Acidophil cell ,medicine.diagnostic_test ,business.industry ,Liver cell ,nutritional and metabolic diseases ,Fibrosis stage ,Middle Aged ,Prognosis ,medicine.disease ,United States ,digestive system diseases ,030104 developmental biology ,Liver ,Hepatocytes ,Positive relationship ,Female ,030211 gastroenterology & hepatology ,Biopsy, Large-Core Needle ,Steatosis ,business - Abstract
The significance of the quantity of acidophil bodies (AB) in nonalcoholic steatohepatitis (NASH) is not certain. We quantified AB in liver biopsies and examined the association with the diagnosis of NASH and other histologic features. We reviewed 157 liver biopsies from the NASH Clinical Research Network Database collected in 2006. One hundred twenty-seven biopsies were from adult patients. Diagnoses were 94 definite NASH, 40 borderline NASH, and 23 definitely not NASH. The total length and average width of the core biopsies were measured, and the biopsy areas were calculated (mm(2)). Total AB were counted, and mean AB count per mm(2) was calculated (AB/mm(2)) to derive acidophil body index (ABI). ABI was 0.04 (±0.08) in definite NASH and 0.02 (±0.05) in borderline/definitely not NASH groups combined (P = .02) in all 157 biopsies; similar findings were present in the 127 adult-only biopsies (0.04 ± 0.05 and 0.02 ± 0.05, respectively; P = .05). In all 157 biopsies, increased ABI was associated with greater lobular inflammation (P = .01) and many ballooned hepatocytes (P = .048). There was a positive relationship between ABI and high nonalcoholic fatty liver disease activity scores, but this association was not statistically significant. There was no association between ABI and steatosis or fibrosis stage either in the entire cohorts or in the subset of adult patients. In conclusion, the density of AB is associated with lobular inflammation, ballooned hepatocytes, and the diagnosis of NASH in adult and pediatric liver biopsies, suggesting the implication of the apoptotic pathway in NASH-associated liver cell injury.
- Published
- 2016
36. Plasminogen Activator Inhibitor-1 Predicts Quantity of Hepatic Steatosis Independent of Insulin Resistance and Body Weight
- Author
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Craig J. McClain, Elizabeth M. Brunt, Jeffrey R. Holzberg, Juna V. Konomi, Gavin E. Arteel, Ngoc-Anh Le, Thomas R. Ziegler, Miriam B. Vos, and Ran Jin
- Subjects
Male ,Pediatric Obesity ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Adolescent ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Overweight ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,Plasminogen Activator Inhibitor 1 ,Nonalcoholic fatty liver disease ,Humans ,Medicine ,Prospective Studies ,Child ,Inflammation ,Anthropometry ,business.industry ,Body Weight ,Gastroenterology ,Acute-phase protein ,medicine.disease ,Fatty Liver ,Endocrinology ,Liver ,chemistry ,Plasminogen activator inhibitor-1 ,Pediatrics, Perinatology and Child Health ,Female ,Insulin Resistance ,Steatosis ,medicine.symptom ,business ,Body mass index ,Plasminogen activator ,Biomarkers - Abstract
The aim of the present study was to examine the association between plasminogen activator inhibitor-1 (PAI-1), an acute phase protein strongly associated with cardiovascular disease risk, and adiposity, insulin resistance, and inflammation among overweight and obese children with a wide range of hepatic steatosis.Plasma PAI-1 levels were measured in a prospectively recruited cohort of 39 overweight or obese children who underwent comprehensive anthropometric assessment and metabolic measurements. Hepatic steatosis was quantified using magnetic resonance spectroscopy and participants were divided into 3 groups based on whether they had normal hepatic steatosis (5%), low hepatic steatosis (≥5%-10%), and high hepatic steatosis (10%).Plasma PAI-1 levels significantly increased across the severity of hepatic steatosis in overweight and obese children, and this association was independent of body mass index z score, visceral fat, insulin resistance, and inflammatory markers (P 0.05).Hepatic steatosis in children is positively associated with circulating levels of PAI-1 independent of body mass index, insulin resistance, and inflammatory markers. Further studies are needed to clarify the potential role of PAI-1 as a therapeutic target in pediatric nonalcoholic fatty liver disease.
- Published
- 2016
37. Terminal hepatic venule injury in liver biopsies of allogeneic haematopoietic stem cell recipients-a study of 63 cases
- Author
-
Elizabeth M. Brunt and Changqing Ma
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Histology ,Hepatic veno-occlusive disease ,Cyclophosphamide ,Biopsy ,medicine.medical_treatment ,Hepatic Veno-Occlusive Disease ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Hepatic Veins ,Liver transplantation ,Gastroenterology ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Venules ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Incidence ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,General Medicine ,Middle Aged ,Total body irradiation ,medicine.disease ,Liver Transplantation ,surgical procedures, operative ,Liver ,030220 oncology & carcinogenesis ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Aims Subtle lesions of terminal hepatic venules (THVs) may be overlooked in liver biopsies from haematopoietic stem cell transplant (HSCT) receipients when graft-versus-host disease is the clinical concern. The aim of this study was to evaluate the frequency of THV injury resembling sinusoidal obstruction syndrome (SOS). Methods and results Sixty-three consecutive biopsies from allogeneic HSCT recipients were scored for injured THVs. Forty-nine (78%) biopsies had injured THVs, and 10 (16%) were diagnosed with SOS (mean ± standard deviation of injured THVs/biopsy: 90 ± 9%). Biopsies diagnosed with other diseases also had injured THVs (36 ± 33%). Biopsies from patients with cyclophosphamide plus fractionated total body irradiation conditioning and biopsies taken within 100 days post-HSCT had significantly more occluded THVs (respectively: 40 ± 38%, P = 0.0188; and 35 ± 35%, P = 0.0076) than those with other conditioning regimens or in biopsies taken >100 days post-HSCT. All biopsies taken at any time in the 6-year post-HSCT period had similar amounts of THV phlebosclerosis (23 ± 25%). Conclusions Our results demonstrate a high incidence of THV injuries resembling SOS in post-HSCT liver biopsies. THV injuries were detectable for several years post-HSCT, and were concurrent with other diagnoses. Our results also suggest that SOS may be underdiagnosed.
- Published
- 2015
38. Complete Response to Erlotinib and Bevacizumab in a Patient With Biphenotypic (Hepatobiliary) Primary Liver Carcinoma
- Author
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Kathryn J. Fowler, Benjamin R. Tan, Elizabeth M. Brunt, Manik Amin, Amy Zhou, and Jesse Keller
- Subjects
Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Bevacizumab ,Biopsy ,Cholangiocarcinoma ,Erlotinib Hydrochloride ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Epidermal growth factor receptor ,Aged ,EGFR inhibitors ,biology ,business.industry ,Liver Neoplasms ,medicine.disease ,Immunohistochemistry ,Magnetic Resonance Imaging ,Vascular endothelial growth factor ,Phenotype ,Treatment Outcome ,chemistry ,Hepatocellular carcinoma ,biology.protein ,Female ,Erlotinib ,business ,Tyrosine kinase ,Biomarkers ,medicine.drug - Abstract
Biphenotypic (hepatobiliary) primary liver carcinomas [B(H-B)PLCs] are rare tumors with features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). These tumors are associated with a poor overall prognosis and treatment is not well defined. Research over the past 20 years has identified aberrations in several molecular pathways, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) in hepatocellular and biliary tract cancers. These discoveries led to the evaluation of targeted therapies, such as tyrosine kinase inhibitors, for the treatment of HCC and ICC. We report a case of a patient with metastatic B(H-B)PLC found to have a single nucleotide variant in the EGFR gene locus R521K who achieved a complete response on imaging after treatment with the combination of an EGFR inhibitor and a VEGF inhibitor. This case prompts consideration of further genomic analysis of these rare tumors and the potential use of targeted therapies in the treatment of patients with B(H-B)PLCs.
- Published
- 2015
39. 324 LIVER SPECIFIC DELETION OF TM6SF2 PROMOTES BOTH HEPATIC FIBROSIS AND HEPATOCELLULAR CANCER
- Author
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Elizabeth A. Molitor, Zoe Hall, Elizabeth M. Brunt, Jules Griffin, Yan Xie, Elizabeth P. Newberry, and Nicholas O. Davidson
- Subjects
Hepatocellular cancer ,Hepatology ,business.industry ,Gastroenterology ,Cancer research ,Medicine ,Hepatic fibrosis ,business ,TM6SF2 - Published
- 2020
40. Sa1556 IMPAIRED INTESTINAL CHYLOMICRON SECRETION DISSOCIATES REVERSAL OF HEPATIC STEATOSIS VERSUS FIBROSIS IN DISTINCT MODELS OF MOUSE NONALCOHOLIC STEATOHEPATITIS BY MODULATING PHOSPHOLIPID REMODELING
- Author
-
Nicholas O. Davidson, Elizabeth M. Brunt, Elizabeth A. Molitor, Kathryn A. Knoop, Yan Xie, and Elizabeth P. Newberry
- Subjects
Nonalcoholic steatohepatitis ,medicine.medical_specialty ,Hepatology ,Chemistry ,Gastroenterology ,Phospholipid ,medicine.disease ,chemistry.chemical_compound ,Endocrinology ,Fibrosis ,Internal medicine ,medicine ,Secretion ,Steatosis ,Chylomicron - Published
- 2020
41. 691 RNA BINDING PROTEIN APOBEC1 COMPLEMENTATION FACTOR (A1CF) ALTERS HEPATIC LIPOGENIC AND PROLIFERATIVE PATHWAYS PROMOTING SPONTANEOUS TUMORIGENESIS
- Author
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Valerie Blanc, ILKe Nalbantoglu, Saeed Soleyman-Jahi, Irene Oi-Lin Ng, Yeonjung Ha, Elizabeth A. Molitor, Lewis R. Roberts, Joseph H. Nadeau, Nicholas O. Davidson, Jesse D. Riordan, Elizabeth M. Brunt, Jason C. Mills, Blair B. Madison, and Yan Xie
- Subjects
Hepatology ,Chemistry ,Gastroenterology ,medicine ,RNA-binding protein ,Carcinogenesis ,medicine.disease_cause ,APOBEC1 complementation factor ,Cell biology - Published
- 2020
42. Frequent GNAQ and GNA14 Mutations in Hepatic Small Vessel Neoplasm
- Author
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ILKe Nalbantoglu, Celia Marginean, Ryan M. Gill, Nancy M. Joseph, Sarah E. Umetsu, Matthew M. Yeh, Linda D. Ferrell, Swan N. Thung, Elizabeth M. Brunt, and Dale C. Snover
- Subjects
0301 basic medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Biology ,Pathology and Forensic Medicine ,Hemangioma ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Vascular Neoplasm ,Humans ,Congenital Hemangioma ,Exome sequencing ,Aged ,GNA11 ,Capillary hemangioma ,Liver Neoplasms ,Middle Aged ,medicine.disease ,030104 developmental biology ,Kaposiform Hemangioendothelioma ,030220 oncology & carcinogenesis ,Mutation ,Neoplasms, Vascular Tissue ,GTP-Binding Protein alpha Subunits, Gq-G11 ,Surgery ,Female ,Anatomy ,GNAQ - Abstract
Hepatic small vessel neoplasm (HSVN) is a recently described infiltrative vascular neoplasm of the liver, composed of small vessels. Although the infiltrative nature can mimic angiosarcoma, HSVN are thought to be benign or low-grade neoplasms because they lack cytologic atypia and increased proliferation. To characterize the molecular pathogenesis of HSVN, we performed both targeted panel sequencing and exome sequencing on 18 benign or low-grade vascular neoplasms in the liver including 8 HSVN, 6 classic cavernous hemangioma (CH), and 4 variant lesions (VL) with overlapping features between HSVN and CH. All 18 lesions had simple genomes without copy number alterations. In total, 75% (6/8) of HSVN demonstrated known activating hotspot mutations in GNAQ (2/8, p.Q209H) or GNA14 (4/8, p.Q205L), and the remaining 2 had the same missense mutation in GNAQ, p.G48L, which has not been previously described. 25% (1/4) of VL had a hotspot GNAQ p.Q209H mutation and another VL had a GNAQ p.G48L mutation. Known pathogenic mutations were not identified in any of the 6 CH. These data suggest that HSVN share a similar molecular biology to several other vascular lesions (congenital hemangioma, tufted angioma, anastomosing hemangioma, lobular capillary hemangioma, and kaposiform hemangioendothelioma) recently reported to have GNAQ, GNA11, or GNA14 mutations.
- Published
- 2018
43. Genetic Variants Associated With Obesity and Insulin Resistance in Hispanic Boys With Nonalcoholic Fatty Liver Disease
- Author
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Katherine P. Yates, Jean P. Molleston, Xiuqing Guo, Rohit Loomba, Mark O. Goodarzi, Naga Chalasani, Soonil Kwon, Jeffrey B. Schwimmer, Joel E. Lavine, Yii-Der Ida Chen, John C. Rausch, Jerome I. Rotter, Elizabeth M. Brunt, and Kent D. Taylor
- Subjects
0301 basic medicine ,Blood Glucose ,Male ,Pediatric Obesity ,Genotyping Techniques ,Genome-wide association study ,030204 cardiovascular system & hematology ,Gastroenterology ,Body Mass Index ,Cohort Studies ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Risk Factors ,Nonalcoholic fatty liver disease ,Prevalence ,Insulin ,Longitudinal Studies ,Prospective Studies ,Prospective cohort study ,Child ,Adiposity ,Hispanic or Latino ,Lipids ,Liver ,Cohort study ,medicine.medical_specialty ,Adolescent ,digestive system ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Insulin resistance ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Glycated Hemoglobin ,business.industry ,nutritional and metabolic diseases ,Genetic Variation ,medicine.disease ,Obesity ,digestive system diseases ,030104 developmental biology ,Pediatrics, Perinatology and Child Health ,Steatohepatitis ,Insulin Resistance ,business ,Body mass index ,Genome-Wide Association Study - Abstract
BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic boys. Further, obesity and insulin resistance are major risk factors for NAFLD. No gene localization studies had been performed on children with biopsy-proven NAFLD. This study aims to identify genomic variants associated with increased adiposity and insulin resistance in a population of children with varying histologic severity of NAFLD. METHODS: We conducted a genome-wide association scan (GWAS) including 624,297 single nucleotide polymorphisms (SNPs) distributed among all 22 autosomal chromosomes in 234 Hispanic boys (up to 18 years of age) who were consecutively recruited in a prospective cohort study in the Nonalcoholic Steatohepatitis Clinical Research Network Studies. Traits were examined quantitatively using linear regression. SNPs with p-value 5% were considered potentially significant. RESULTS: Evaluated subjects had a median age of 12.0 years, BMI of 31.4, and hemoglobin A1C (Hgb A1C) of 5.3. The prevalence of NAFL, borderline NASH and definite NASH were 23%, 53%, and 22%, respectively. The GWAS identified 10 SNPs that were associated with BMI z-score, 6 within chromosome 2, and 1 within CAMK1D, which has a potential role in liver gluconeogenesis. In addition, the GWAS identified 9 novel variants associated with insulin resistance: HOMA-IR (6) and HbA1c (3). CONCLUSIONS: This study of Hispanic boys with biopsy-proven NAFLD with increased risk for the metabolic syndrome revealed novel genetic variants that are associated with obesity and insulin resistance.
- Published
- 2018
44. Assessment of Liver Histology
- Author
-
Elizabeth M. Brunt
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Medicine ,business ,Liver histology - Published
- 2018
45. Contributors
- Author
-
Nezam H. Afdhal, Alina M. Allen, Aditya Ambade, Quentin M. Anstee, Sumeet K. Asrani, Davis N. Assis, Jasmohan Singh Bajaj, William F. Balistreri, Jesus M. Banales, Richard Bendall, Ariel Benson, Antonio Bertoletti, Jorge A. Bezerra, Scott W. Biggins, Herbert L. Bonkovsky, Christopher Bowlus, Thomas D. Boyer, David A. Brenner, Elizabeth M. Brunt, Stephen H. Caldwell, Naga Chalasani, Jonathan R. Cogley, Massimo Colombo, Min Cong, David W. Crabb, James M. Crawford, Harry R. Dalton, Srinivasan Dasarathy, Christopher P. Day, Laurie D. DeLeve, Kalpana M. Devaraj, Harshad Devarbhavi, Anna Mae Diehl, Joost P.H. Drenth, Razan El Ramahi, Tamer Mahmoud Elbaz, Laure Elkrief, Gamal Esmat, Gregory Thomas Everson, Phillip Factor, Michael B. Fallon, Sandy Feng, Stuart Forbes, Bin Gao, Guadalupe Garcia-Tsao, Aiman Ghufran, Patrick Martin Gillevet, Jeffrey S. Glenn, David Goldberg, Stuart C. Gordon, Gregory J. Gores, Shahid Habib, Stephen A. Harrison, Theo Heller, Steve M. Helmke, Deborah Holtzman, Nicolas M. Intagliata, Jacques Izopet, Syed-Mohammed Jafri, Harry L.A. Janssen, Jidong Jia, Bobby T. Kalb, Patrick S. Kamath, Saul J. Karpen, Constantine J. Karvellas, Tatiana Kisseleva, Stephen A. Klotz, Christopher Koh, Rohit Kohli, Monica A. Konerman, Shyamasundaran Kottilil, Laura Kulik, Asha C. Kuruvilla, Frank Lammert, Konstantinos N. Lazaridis, Riccardo Lencioni, Cynthia Levy, Hongxia Li, Suthat Liangpunsakul, Ansgar W. Lohse, Anna S. Lok, Georgios Loudianos, Michael R. Lucey, Mariana Verdelho Machado, Diego R. Martin, Eric G. Meissner, Frank H. Miller, Andrew J. Muir, Moises I. Nevah, Erin K. O'Neill, Ran Oren, Kavish R. Patidar, Mark M. Pence, David Perlmutter, Antonello Pietrangelo, Stacey Prenner, Puneet Puri, Lihui Qin, Nataliya Razumilava, Jurrien Reijnders, Eve A. Roberts, Lewis R. Roberts, Jayanta Roy-Chowdhury, Namita Roy-Chowdhury, Mark Russo, Sammy Saab, Banishree Saha, Angelo Sangiovanni, Varun Saxena, Kathleen B. Schwarz, Seth N. Sclair, Susana Seijo, Kenneth D.R. Setchell, Vijay H. Shah, Obaid S. Shaikh, Kenneth E. Sherman, Douglas A. Simonetto, Ashwani K. Singal, Milan Sonneveld, James E. Squires, Richard K. Sterling, Amy N. Stratton, R. Todd Stravitz, Stephen Strom, Gyongyi Szabo, Jayant A. Talwalkar, Lydia Tang, Elliot B. Tapper, Norah A. Terrault, Dawn M. Torres, Parsia A. Vagefi, Dominique C. Valla, Douglas C. Vander Kooi, John W. Ward, Joel P. Wedd, Christina Weiler-Normann, Florence Wong, Ju Dong Yang, Samir Zakhari, Tirdad T. Zangeneh, Naglaa Zayed, and Fabien Zoulim
- Published
- 2018
46. Genome-Wide Associations Related to Hepatic Histology in Nonalcoholic Fatty Liver Disease in Hispanic Boys
- Author
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Joel E. Lavine, Julia Wattacheril, James Tonascia, Jerome I. Rotter, Rohit Loomba, Naga Chalasani, Mark O. Goodarzi, Soonil Kwon, Elizabeth M. Brunt, Jean P. Molleston, Kent D. Taylor, Katherine P. Yates, Xiuqing Guo, Yii-Der Ida Chen, and Jeffrey B. Schwimmer
- Subjects
0301 basic medicine ,Male ,Pathology ,Databases, Factual ,Hispanic ,Genome-wide association study ,Gastroenterology ,Oral and gastrointestinal ,Hepatitis ,Non-alcoholic Fatty Liver Disease ,Nonalcoholic fatty liver disease ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Liver Disease ,Fatty liver ,Single Nucleotide ,Hispanic or Latino ,Liver ,Child, Preschool ,Cohort ,Hispanic Americans ,medicine.medical_specialty ,Genotype ,Adolescent ,pediatrics ,Chronic Liver Disease and Cirrhosis ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Article ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Databases ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,Genetics ,SNP ,Humans ,Polymorphism ,Preschool ,Factual ,Genetic association ,fatty liver ,business.industry ,Prevention ,fibrosis ,Human Genome ,genome wide ,Human Movement and Sports Sciences ,medicine.disease ,030104 developmental biology ,Good Health and Well Being ,Pediatrics, Perinatology and Child Health ,business ,Digestive Diseases ,Body mass index ,Genome-Wide Association Study - Abstract
Objective To identify genetic loci associated with features of histologic severity of nonalcoholic fatty liver disease in a cohort of Hispanic boys. Study design There were 234 eligible Hispanic boys age 2-17 years with clinical, laboratory, and histologic data enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network included in the analysis of 624 297 single nucleotide polymorphisms (SNPs). After the elimination of 4 outliers and 22 boys with cryptic relatedness, association analyses were performed on 208 DNA samples with corresponding liver histology. Logistic regression analyses were carried out for qualitative traits and linear regression analyses were applied for quantitative traits. Results The median age and body mass index z-score were 12.0 years (IQR, 11.0-14.0) and 2.4 (IQR, 2.1-2.6), respectively. The nonalcoholic fatty liver disease activity score (scores 1-4 vs 5-8) was associated with SNP rs11166927 on chromosome 8 in the TRAPPC9 region (P = 8.7-07). Fibrosis stage was associated with SNP rs6128907 on chromosome 20, near actin related protein 5 homolog (p = 9.9-07). In comparing our results in Hispanic boys with those of previously reported SNPs in adult nonalcoholic steatohepatitis, 2 of 26 susceptibility loci were associated with nonalcoholic fatty liver disease activity score and 2 were associated with fibrosis stage. Conclusions In this discovery genome-wide association study, we found significant novel gene effects on histologic traits associated with nonalcoholic fatty liver disease activity score and fibrosis that are distinct from those previously recognized by adult nonalcoholic fatty liver disease genome-wide association studies.
- Published
- 2017
47. Magnetic resonance elastography measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic fatty liver disease
- Author
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Jorge E. Angeles, Claude B. Sirlin, Kelvin K. Wong, Janis Durelle, Stephanie H. Abrams, Melissa Paiz, Michael S. Middleton, Kevin J. Glaser, Prakash Masand, Elizabeth M. Brunt, Kimberly P. Newton, Rajesh Krishnamurthy, William Haufe, Gavin Hamilton, Jonathan A. Africa, Meng Yin, Tanya Wolfson, Cynthia Behling, Alexandra Schlein, Jeffrey B. Schwimmer, Joel E. Lavine, Bogdan Dzyubak, Jonathan Hooker, Richard L. Ehman, and Anthony Gamst
- Subjects
Liver Cirrhosis ,Male ,medicine.medical_specialty ,Adolescent ,Cross-sectional study ,Chronic Liver Disease and Cirrhosis ,Clinical Sciences ,Immunology ,Medical Biochemistry and Metabolomics ,Article ,Oral and gastrointestinal ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Non-alcoholic Fatty Liver Disease ,Clinical Research ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Child ,Pediatric ,screening and diagnosis ,Hepatology ,Gastroenterology & Hepatology ,business.industry ,Liver Disease ,medicine.disease ,Confidence interval ,Magnetic resonance elastography ,Surgery ,Detection ,Cross-Sectional Studies ,Liver ,Biomarker (medicine) ,Elasticity Imaging Techniques ,Biomedical Imaging ,030211 gastroenterology & hepatology ,Female ,Radiology ,business ,Digestive Diseases ,Biomarkers ,4.2 Evaluation of markers and technologies - Abstract
Magnetic resonance elastography (MRE) is a promising technique for noninvasive assessment of fibrosis, a major determinant of outcome in nonalcoholic fatty liver disease (NAFLD). However, data in children are limited. The purpose of this study was to determine the accuracy of MRE for the detection of fibrosis and advanced fibrosis in children with NAFLD and to assess agreement between manual and novel automated reading methods. We performed a prospective, multicenter study of two-dimensional (2D) MRE in children with NAFLD. MR elastograms were analyzed manually at two reading centers, and using a new automated technique. Analysis using each approach was done independently. Correlations were determined between MRE analysis methods and fibrosis stage. Thresholds for classifying the presence of fibrosis and of advanced fibrosis were computed and cross-validated. In 90 children with a mean age of 13.1 ± 2.4 years, median hepatic stiffness was 2.35 kPa. Stiffness values derived by each reading center were strongly correlated with each other (r = 0.83). All three analyses were significantly correlated with fibrosis stage (center 1, ρ = 0.53; center 2, ρ = 0.55; and automated analysis, ρ = 0.52; P
- Published
- 2017
48. Anatomic Pathology of Hepatocellular Carcinoma
- Author
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Meredith E. Pittman and Elizabeth M. Brunt
- Subjects
medicine.medical_specialty ,Pathology ,Hepatology ,medicine.diagnostic_test ,business.industry ,Anatomical pathology ,Diagnostic tools ,medicine.disease ,Glypican 3 ,Liver biopsy ,Hepatocellular carcinoma ,Needle biopsy ,medicine ,Histopathology ,Radiology ,business ,Liver histology - Abstract
Hepatocellular carcinoma can be diagnosed on a needle biopsy of the liver; however, uncertainty may arise because of the inherent complexity of liver histology. This article aims to provide practicing pathologists with tools for the approach to mass-directed liver biopsies clinically concerning for hepatocellular carcinoma. The examination of routine hematoxylin-eosin stains and the use of ancillary histochemical and immunohistochemical stains are discussed. Sections reviewing liver carcinoma with biphenotypic differentiation and the challenge of dysplastic nodules are included.
- Published
- 2015
49. Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD
- Author
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Michele Donithan, Jessica Bazick, Brent A. Neuschwander-Tetri, Ed Doo, Laura A. Wilson, Joel E. Lavine, James Tonascia, Rohit Loomba, Elizabeth M. Brunt, and David E. Kleiner
- Subjects
Adult ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cross-sectional study ,Endocrinology, Diabetes and Metabolism ,Type 2 diabetes ,Hematocrit ,Medical and Health Sciences ,digestive system ,Sensitivity and Specificity ,Gastroenterology ,Decision Support Techniques ,Endocrinology & Metabolism ,Insulin resistance ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Diabetes mellitus ,Nonalcoholic fatty liver disease ,Diabetes Mellitus ,Prevalence ,Internal Medicine ,medicine ,Humans ,Pathophysiology/Complications ,Referral and Consultation ,Aged ,Advanced and Specialized Nursing ,Receiver operating characteristic ,medicine.diagnostic_test ,business.industry ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,United States ,digestive system diseases ,3. Good health ,Surgery ,Cross-Sectional Studies ,Diabetes Mellitus, Type 2 ,Practice Guidelines as Topic ,Cohort ,Female ,business ,Type 2 - Abstract
OBJECTIVE Approximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment. RESEARCH DESIGN AND METHODS This study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI. RESULTS The mean ± SD age and BMI of patients with diabetes and NAFLD was 52.5 ± 10.3 years and 35.8 ± 6.8 kg/m2, respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA1c, HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75–0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit, international normalized ratio, and platelet count with an AUROC of 0.80 (95% CI 0.76–0.85, P < 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis. CONCLUSIONS Routinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists.
- Published
- 2015
50. Polypoid Lesions of the Gallbladder: Disease Spectrum with Pathologic Correlation
- Author
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Vincent M. Mellnick, Amy K. Hara, Kumar Sandrasegaran, Ania Z. Kielar, Nirvikar Dahiya, Elizabeth M. Brunt, Khaled M. Elsayes, Christine O. Menias, and M.B. Majella Doyle
- Subjects
Adult ,Diagnostic Imaging ,Male ,Pathology ,medicine.medical_specialty ,Gallbladder disease ,Gallbladder Diseases ,Lesion ,Polyps ,Pathologic correlation ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Aged ,Aged, 80 and over ,business.industry ,Gallbladder ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Female ,Gallbladder Neoplasms ,Radiology ,medicine.symptom ,business ,Algorithms - Abstract
Gallbladder polyps are seen on as many as 7% of gallbladder ultrasonographic images. The differential diagnosis for a polypoid gallbladder mass is wide and includes pseudotumors, as well as benign and malignant tumors. Tumefactive sludge may be mistaken for a gallbladder polyp. Pseudotumors include cholesterol polyps, adenomyomatosis, and inflammatory polyps, and they occur in that order of frequency. The most common benign and malignant tumors are adenomas and primary adenocarcinoma, respectively. Polyp size, shape, and other ancillary imaging findings, such as a wide base, wall thickening, and coexistent gallstones, are pertinent items to report when gallbladder polyps are discovered. These findings, as well as patient age and risk factors for gallbladder cancer, guide clinical decision making. Symptomatic polyps without other cause for symptoms, an age over 50 years, and the presence of gallstones are generally considered indications for cholecystectomy. Incidentally noted pedunculated polyps smaller than 5 mm generally do not require follow-up. Polyps that are 6-10 mm require follow-up, although neither the frequency nor the length of follow-up has been established. Polyps that are larger than 10 mm are typically excised, although lower size thresholds for cholecystectomy may be considered for patients with increased risk for gallbladder carcinoma, such as patients with primary sclerosing cholangitis.
- Published
- 2015
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