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Njei B, Mezzacappa C, John BV, Serper M, Kaplan DE, Taddei TH, Mahmud N. Mortality, Hepatic Decompensation, and Cardiovascular Outcomes in Lean vs. Non-lean MASLD Cirrhosis: A Veterans Affairs Cohort Study. Dig Dis Sci 2025; 70:802-813. [PMID: 39779587 PMCID: PMC11839701 DOI: 10.1007/s10620-024-08764-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/17/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND AND AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) has a global prevalence of 25%. Studies on incident liver and cardiovascular outcomes in lean (Body mass index: BMI < 25 kg/m2, or < 23 kg/m2 for Asians) vs. non-lean individuals with MASLD have reported mixed results. We aimed to compare incident clinical outcomes and mortality between lean and non-lean individuals with compensated MASLD cirrhosis in a large national cohort. METHODS This was a retrospective cohort study of patients with newly diagnosed compensated MASLD cirrhosis in the Veterans Health Administration between 01/2008 and 05/2021. The primary outcome was incident hepatic decompensation, and secondary outcomes were incident major adverse cardiovascular events (MACE) and all-cause mortality. Multivariable Cox proportional hazard models were used to assess association. Fine and Gray competing risk regression was used where applicable. RESULTS The study included 15155 patients with MASLD cirrhosis: 1,597 lean and 13558 non-lean patients. Included patients were mostly male (95%), median age was 67 years, and 72.8% were non-Hispanic white. At baseline, the prevalence of diabetes was lower in lean vs. non-lean individuals (46.7 vs. 73.9%, p < 0.001). In multivariable models, lean status was associated with a 64% increased risk of all-cause mortality (aHR = 1.64) but decreased risk of hepatic decompensation (aSHR = 0.67). Lean individuals experienced significantly higher rates of cardiovascular-related mortality (aHR = 1.40). CONCLUSION Lean MASLD patients with compensated cirrhosis had a higher mortality risk but a lower risk of hepatic decompensation than non-lean patients. Despite having a better baseline cardiometabolic profile and similar rates of MACE, lean individuals with MASLD cirrhosis have a higher risk of cardiovascular mortality.
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Affiliation(s)
- Basile Njei
- Section of Digestive Diseases, Yale University School of Medicine/VA Connecticut Healthcare System, New Haven, CT, USA
| | - Catherine Mezzacappa
- Section of Digestive Diseases, Yale University School of Medicine/VA Connecticut Healthcare System, New Haven, CT, USA
| | - Binu V John
- University of Miami and Miami VA Health System, Miami, FL, USA
| | | | - David E Kaplan
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Tamar H Taddei
- Section of Digestive Diseases, Yale University School of Medicine/VA Connecticut Healthcare System, New Haven, CT, USA
| | - Nadim Mahmud
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
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Mischel AK, Liao Z, Cao F, Dunn W, Lo JC, Newton KP, Goyal NP, Yu EL, Schwimmer JB. Prevalence of Elevated ALT in Adolescents in the US 2011-2018. J Pediatr Gastroenterol Nutr 2023; 77:103-109. [PMID: 37084344 PMCID: PMC10330162 DOI: 10.1097/mpg.0000000000003795] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/23/2023]
Abstract
OBJECTIVE The objective of this study is to characterize suspected nonalcoholic fatty liver disease (NAFLD) using elevated alanine aminotransferase (ALT) in a diverse and nationally representative cohort of adolescents and to characterize higher ALT elevation in adolescents with obesity. METHODS Data from the National Health and Nutrition Examination Survey 2011-2018 were analyzed for adolescents 12-19 years. Participants with causes for elevated ALT other than NAFLD were excluded. Race and ethnicity, sex, body mass index (BMI), and ALT were examined. Elevated ALT was defined as >22 U/L (females) and >26 U/L (males) using the biologic upper normal limit (ULN). Elevated ALT thresholds up to 2X-ULN were examined among adolescents with obesity. Multivariable logistic regression was used to determine the association of race/ethnicity and elevated ALT, adjusting for age, sex, and BMI. RESULTS Prevalence of elevated ALT in adolescents was 16.5% overall and 39.5% among those with obesity. For White, Hispanic, and Asian adolescents, prevalence was 15.8%, 21.8%, and 16.5% overall, 12.8%, 17.7%, and 27.0% in those with overweight, and 43.0%, 43.5%, and 43.1% in those with obesity, respectively. Prevalence was much lower in Black adolescents (10.7% overall, 8.4% for overweight, 20.7% for obesity). Prevalence of ALT at 2X-ULN was 6.6% in adolescents with obesity. Hispanic ethnicity, age, male sex, and higher BMI were independent predictors of elevated ALT. CONCLUSIONS Prevalence of elevated ALT in U.S. adolescents is high, affecting 1 in 6 adolescents during 2011-2018. The risk is highest in Hispanic adolescents. Asian adolescents with elevated BMI may comprise an emerging risk group for elevated ALT.
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Affiliation(s)
- Anna K. Mischel
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, CA, 92093, USA
| | - Zhengxu Liao
- Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego School of Medicine, La Jolla, CA, 92093, USA
| | - Fangyi Cao
- Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego School of Medicine, La Jolla, CA, 92093, USA
| | - Winston Dunn
- Gastroenterology and Hepatology, the University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Joan C. Lo
- Department of Medicine, Kaiser Permanente Oakland Medical Center, 3600 Broadway, Oakland, Ca, 94611, USA
- Division of Research, Kaiser Permanente Northern California, 2000- Broadway, Oakland, CA, 94612, USA
| | - Kimberly P. Newton
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, CA, 92093, USA
- Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, CA, 92123, USA
| | - Nidhi P. Goyal
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, CA, 92093, USA
- Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, CA, 92123, USA
| | - Elizabeth L. Yu
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, CA, 92093, USA
- Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, CA, 92123, USA
| | - Jeffrey B. Schwimmer
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, CA, 92093, USA
- Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, CA, 92123, USA
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3
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Diagnostic performance of ultrasound hepatorenal index for the diagnosis of hepatic steatosis in children. Pediatr Radiol 2022; 52:1306-1313. [PMID: 35229183 DOI: 10.1007/s00247-022-05313-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 12/29/2021] [Accepted: 02/03/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is increasing in prevalence and is the most common cause of pediatric chronic liver disease. Objective US-based measures of hepatic steatosis are an unmet clinical need. OBJECTIVE To evaluate the diagnostic performance of quantitative measurement of liver echogenicity (hepatorenal index, or HRI) for hepatic steatosis in a pediatric cohort. MATERIALS AND METHODS We identified pediatric patients (≤18 years old) who underwent both clinically indicated abdominal US and MRI with liver proton-density fat fraction (PDFF) within the 3-month period during the timeframe of July 2015-April 2020 (n=69). Using ImageJ, we drew small circular regions of interest (ROIs) and large freehand ROIs in the liver and right kidney on single longitudinal and transverse images to measure echogenicity (arbitrary units). We calculated four HRIs (liver-to-kidney ratio) as well as liver histogram features. Five pediatric radiologists independently reported the qualitative presence/absence of hepatic steatosis. We used Pearson correlation (r) to assess associations and receiver operating characteristic (ROC) curve analyses to evaluate diagnostic performance. Multivariable logistic regression was used to further assess relationships. RESULTS Mean patient age was 11.6 (standard deviation [SD] 4.7, range 0.3-18) years; 27/69 (39.1%) were female. Mean PDFF was 12.5% (SD 13.1%, range 1-48%); 34/69 (49.3%) patients were classified as having hepatic steatosis by MRI (PDFF ≥6%). There were significant, positive correlations between all four US HRI methods and PDFF (r=0.51-0.61); longitudinal freehand ROIs exhibited the strongest correlation (r=0.61; P<0.0001). Longitudinal freehand ROI HRI had moderate diagnostic performance for the binary presence of steatosis (area under the curve [AUC]=0.80, P<0.0001), with an optimal cut-off value >1.75 (sensitivity=70.6%, specificity=77.1%). Radiologists' sensitivity for detecting hepatic steatosis ranged from 79.4% to 97.1%, and specificity ranged from 91.2% to 100%. Significant multivariable predictors of PDFF ≥6% included HRI (P=0.002; odds ratio [OR]=34.2), body mass index (BMI) percentile (P=0.005; OR=1.06), and liver gray-scale echogenicity standard deviation (P=0.02; OR=0.79) (receiver operating characteristic AUC = 0.92). CONCLUSION Quantitative US HRI has moderate diagnostic performance for detecting liver fat in children and positively correlates with MRI PDFF. Incorporation of BMI-percentile and gray-scale echogenicity standard deviation improved diagnostic performance.
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Kohut T, Serai S, Panganiban J. Utilization of Topiramate as an Adjunct to Lifestyle Intervention for Weight Loss in Pediatric Nonalcoholic Fatty Liver Disease. JPGN REPORTS 2021; 2:e126. [PMID: 37206463 PMCID: PMC10191479 DOI: 10.1097/pg9.0000000000000126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 09/02/2021] [Indexed: 05/21/2023]
Abstract
Nonalcoholic fatty liver disease is the most common chronic liver disease in children and has become the leading indication for liver transplantation in adults. The primary treatment modality is lifestyle modification to promote weight loss, which is challenging to achieve and maintain. Adjunctive weight loss medications, such as topiramate, are commonly used off-label in adults and children with obesity and found to be safe and effective. We report an adolescent male with severe obesity and nonalcoholic steatohepatitis refractory to aggressive lifestyle intervention. He was safely treated with topiramate with resultant weight loss, reduction in body mass index z-score, improvement in liver enzymes, and resolution of hepatic steatosis. This is the first report of using topiramate in a pediatric patient with obesity and nonalcoholic steatohepatitis. Topiramate should be considered in pediatric nonalcoholic fatty liver disease to help curb emotional eating and promote satiety in cases refractory to lifestyle intervention alone.
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Affiliation(s)
- Taisa Kohut
- From the Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Suraj Serai
- Department of Radiology, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Jennifer Panganiban
- From the Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA
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5
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Zhao R, Hernando D, Harris DT, Hinshaw LA, Li K, Ananthakrishnan L, Bashir MR, Duan X, Ghasabeh MA, Kamel IR, Lowry C, Mahesh M, Marin D, Miller J, Pickhardt PJ, Shaffer J, Yokoo T, Brittain JH, Reeder SB. Multisite multivendor validation of a quantitative MRI and CT compatible fat phantom. Med Phys 2021; 48:4375-4386. [PMID: 34105167 DOI: 10.1002/mp.15038] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 03/15/2021] [Accepted: 05/26/2021] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Chemical shift-encoded magnetic resonance imaging enables accurate quantification of liver fat content though estimation of proton density fat-fraction (PDFF). Computed tomography (CT) is capable of quantifying fat, based on decreased attenuation with increased fat concentration. Current quantitative fat phantoms do not accurately mimic the CT number of human liver. The purpose of this work was to develop and validate an optimized phantom that simultaneously mimics the MRI and CT signals of fatty liver. METHODS An agar-based phantom containing 12 vials doped with iodinated contrast, and with a granular range of fat fractions was designed and constructed within a novel CT and MR compatible spherical housing design. A four-site, three-vendor validation study was performed. MRI (1.5T and 3T) and CT images were obtained using each vendor's PDFF and CT reconstruction, respectively. An ROI centered in each vial was placed to measure MRI-PDFF (%) and CT number (HU). Mixed-effects model, linear regression, and Bland-Altman analysis were used for statistical analysis. RESULTS MRI-PDFF agreed closely with nominal PDFF values across both field strengths and all MRI vendors. A linear relationship (slope = -0.54 ± 0.01%/HU, intercept = 37.15 ± 0.03%) with an R2 of 0.999 was observed between MRI-PDFF and CT number, replicating established in vivo signal behavior. Excellent test-retest repeatability across vendors (MRI: mean = -0.04%, 95% limits of agreement = [-0.24%, 0.16%]; CT: mean = 0.16 HU, 95% limits of agreement = [-0.15HU, 0.47HU]) and good reproducibility using GE scanners (MRI: mean = -0.21%, 95% limits of agreement = [-1.47%, 1.06%]; CT: mean = -0.18HU, 95% limits of agreement = [-1.96HU, 1.6HU]) were demonstrated. CONCLUSIONS The proposed fat phantom successfully mimicked quantitative liver signal for both MRI and CT. The proposed fat phantom in this study may facilitate broader application and harmonization of liver fat quantification techniques using MRI and CT across institutions, vendors and imaging platforms.
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Affiliation(s)
- Ruiyang Zhao
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
| | - Diego Hernando
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
| | - David T Harris
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA
| | - Louis A Hinshaw
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
| | - Ke Li
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
| | | | - Mustafa R Bashir
- Department of Radiology, Duke University, Durham, NC, USA.,Center for Advanced Magnetic Resonance Development, Duke University, Durham, NC, USA.,Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA
| | - Xinhui Duan
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Ihab R Kamel
- Department of Radiology, Johns Hopkins University, Baltimore, MD, USA
| | - Carolyn Lowry
- Department of Radiology, Duke University, Durham, NC, USA
| | | | - Daniele Marin
- Department of Radiology, Duke University, Durham, NC, USA
| | - Jessica Miller
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA
| | - Perry J Pickhardt
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA
| | - Jean Shaffer
- Department of Radiology, Duke University, Durham, NC, USA.,Center for Advanced Magnetic Resonance Development, Duke University, Durham, NC, USA
| | - Takeshi Yokoo
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Scott B Reeder
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA.,Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medicine, University of Wisconsin, Madison, WI, USA.,Department of Emergency Medicine, University of Wisconsin-Madison, Madison, WI, USA
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6
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Okushin K, Tsutsumi T, Ikeuchi K, Kado A, Enooku K, Fujinaga H, Yamauchi N, Ushiku T, Moriya K, Yotsuyanagi H, Koike K. Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet. PLoS One 2020; 15:e0234750. [PMID: 32785220 PMCID: PMC7423142 DOI: 10.1371/journal.pone.0234750] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/01/2020] [Indexed: 12/15/2022] Open
Abstract
The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, including in Asian countries. We reported that the hepatic expression of bile salt export pump (BSEP) was downregulated in patients with NASH, suggesting that BSEP is involved in the pathogenesis of NASH. To identify the underlying mechanism, we analyzed Bsep heterozygous knock-out (Bsep+/- mice) and wild-type (WT) C57BL/6J mice fed a high-fat diet (HFD) (32.0% animal fat) or normal diet. We examined histological changes, levels of hepatic lipids and hepatic bile acids, and expression of genes related to bile acid and cholesterol metabolism. HFD-fed Bsep+/- mice exhibited milder hepatic steatosis and less weight gain, compared to HFD-fed WT mice. The concentrations of total bile acid, triglycerides, and cholesterols were reduced in the liver of HFD-fed Bsep+/- mice. Regarding hepatic bile acid metabolism, the expression levels of Farnesoid X receptor (Fxr) and Multidrug resistance-associated protein 2 were significantly upregulated in HFD-fed Bsep+/- mice, compared to HFD-fed WT mice. Furthermore, several alterations were observed in upstream cholesterol metabolism in the liver. The expression levels of bile acid metabolism-related genes were also altered in the intestine of HFD-fed Bsep+/- mice. In conclusion, HFD-fed Bsep+/- mice exhibited significant alterations of the expression levels of genes related to bile acid and lipid metabolism in both the liver and ileum, resulting in alleviated steatosis and less weight gain. These results suggest the importance of BSEP for maintenance of bile acid and cholesterol metabolism. Further investigations of the involvement of BSEP in the pathogenesis of NASH will provide greater insight and facilitate the development of novel therapeutic modalities.
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Affiliation(s)
- Kazuya Okushin
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Ikeuchi
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Akira Kado
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kenichiro Enooku
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hidetaka Fujinaga
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoko Yamauchi
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kyoji Moriya
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- * E-mail:
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7
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Zhao R, Zhang Y, Wang X, Colgan TJ, Rehm JL, Reeder SB, Johnson KM, Hernando D. Motion-robust, high-SNR liver fat quantification using a 2D sequential acquisition with a variable flip angle approach. Magn Reson Med 2020; 84:2004-2017. [PMID: 32243665 DOI: 10.1002/mrm.28263] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/24/2020] [Accepted: 03/02/2020] [Indexed: 01/18/2023]
Abstract
PURPOSE Chemical shift encoded (CSE)-MRI enables quantification of proton-density fat fraction (PDFF) as a biomarker of liver fat content. However, conventional 3D Cartesian CSE-MRI methods require breath-holding. A motion-robust 2D Cartesian sequential method addresses this limitation but suffers from low SNR. In this work, a novel free breathing 2D Cartesian sequential CSE-MRI method using a variable flip angle approach with centric phase encoding (VFA-centric) is developed to achieve fat quantification with low T 1 bias, high SNR, and minimal blurring. METHODS Numerical simulation was performed for variable flip angle schedule design and preliminary evaluation of VFA-centric method, along with several alternative flip angle designs. Phantom, adults (n = 8), and children (n = 27) were imaged at 3T. Multi-echo images were acquired and PDFF maps were estimated. PDFF standard deviation was used as a surrogate for SNR. RESULTS In both simulation and phantom experiments, the VFA-centric method enabled higher SNR imaging with minimal T 1 bias and blurring artifacts. High correlation (slope = 1.00, intercept = 0.04, R 2 = 0.998) was observed in vivo between the proposed VFA-centric method obtained PDFF and reference PDFF (free breathing low-flip angle 2D sequential acquisition). Further, the proposed VFA-centric method (PDFF standard deviation = 1.5%) had a better SNR performance than the reference acquisition (PDFF standard deviation = 3.3%) with P < .001. CONCLUSIONS The proposed free breathing 2D Cartesian sequential CSE-MRI method with variable flip angle approach and centric-ordered phase encoding achieved motion robustness, low T 1 bias, high SNR compared to previous 2D sequential methods, and low blurring in liver fat quantification.
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Affiliation(s)
- Ruiyang Zhao
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
| | - Yuxin Zhang
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
| | - Xiaoke Wang
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
| | - Timothy J Colgan
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
| | - Jennifer L Rehm
- Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, USA
| | - Scott B Reeder
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA.,Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.,Department of Emergency Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Kevin M Johnson
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
| | - Diego Hernando
- Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.,Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
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Abstract
PURPOSE OF REVIEW We aim to describe current concepts on childhood and adolescent obesity with a strong focus on its sequela. Childhood obesity is a national epidemic with increasing prevalence over the past three decades placing children at increased risk for many serious comorbidities, previously felt to be only adult-specific diseases, making this topic both timely and relevant for general pediatricians as well as for subspecialists. RECENT FINDINGS Childhood obesity develops through an interplay of genetics, environment, and behavior. Treatment includes lifestyle modification, and now metabolic and bariatric surgery is more commonly considered in carefully selected adolescents. The off-label use of adjunct medications for weight loss in childhood and adolescent obesity is still in its infancy, but will likely become the next logical step in those with lifestyle modification refractory obesity. Obesity can lead to several comorbidities, which can persist into adulthood potentially shortening the child's lifespan. SUMMARY Efforts should be focused primarily on reducing childhood and adolescent obesity, and when indicated treating its sequela in effort to reduce future morbidity and mortality in this precious population. VIDEO ABSTRACT: http://links.lww.com/MOP/A36.
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9
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Okushin K, Tsutsumi T, Ikeuchi K, Kado A, Enooku K, Fujinaga H, Moriya K, Yotsuyanagi H, Koike K. Helicobacter pylori infection and liver diseases: Epidemiology and insights into pathogenesis. World J Gastroenterol 2018; 24:3617-3625. [PMID: 30166857 PMCID: PMC6113725 DOI: 10.3748/wjg.v24.i32.3617] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/30/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Both Helicobacter pylori (H. pylori) infection and liver diseases, including nonalcoholic fatty liver disease (NAFLD), viral hepatitis, and hepatocellular carcinoma (HCC), have high prevalences worldwide, and the relationship between H. pylori infection and liver disease has been discussed for many years. Although positive correlations between H. pylori and NAFLD have been identified in some clinical and experimental studies, negative correlations have also been obtained in high-quality clinical studies. Associations between H. pylori and the pathogenesis of chronic viral hepatitis, mainly disease progression with fibrosis, have also been suggested in some clinical studies. Concerning HCC, a possible role for H. pylori in hepatocarcinogenesis has been identified since H. pylori genes have frequently been detected in resected HCC specimens. However, no study has revealed the direct involvement of H. pylori in promoting the development of HCC. Although findings regarding the correlations between H. pylori and liver disease pathogenesis have been accumulating, the existing data do not completely lead to an unequivocal conclusion. Further high-quality clinical and experimental analyses are necessary to evaluate the efficacy of H. pylori eradication in ameliorating the histopathological changes observed in each liver disease.
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Affiliation(s)
- Kazuya Okushin
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Kazuhiko Ikeuchi
- Department of Infectious Diseases, The University of Tokyo, Tokyo 113-8655, Japan
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Akira Kado
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kenichiro Enooku
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Hidetaka Fujinaga
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kyoji Moriya
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Department of Infectious Diseases, The University of Tokyo, Tokyo 113-8655, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
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10
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Middleton MS, Van Natta ML, Heba ER, Alazraki A, Trout AT, Masand P, Brunt EM, Kleiner DE, Doo E, Tonascia J, Lavine JE, Shen W, Hamilton G, Schwimmer JB, Sirlin CB, for the NASH Clinical Research Network. Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease. Hepatology 2018; 67:858-872. [PMID: 29028128 PMCID: PMC6211296 DOI: 10.1002/hep.29596] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 09/11/2017] [Accepted: 10/12/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED 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 (mean ± SD) values were 10.9 ± 4.1%, 18.4 ± 6.2%, and 25.7 ± 9.7%, 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 (mean ± SD) changes of -7.8 ± 6.3%, -1.2 ± 7.8%, and 4.9 ± 5.0%, 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. CONCLUSION MRI-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).
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Affiliation(s)
- Michael S. Middleton
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, California
| | - Mark L. Van Natta
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Elhamy R. Heba
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, California
| | - Adina Alazraki
- Emory University School of Medicine, Department of Radiology and Imaging Sciences, Atlanta, Georgia
| | - Andrew T. Trout
- Cincinnati Children’s Hospital, Department of Radiology, Cincinnati, Ohio
| | | | | | | | - Edward Doo
- Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases
| | - James Tonascia
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Joel E. Lavine
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Medical Center, New York, New York
| | - Wei Shen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Medical Center, New York, New York
| | - Gavin Hamilton
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, California
| | - Jeffrey B. Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California; and Department of Gastroenterology, Rady Children’s Hospital, San Diego, California
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, California
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11
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Yokoo T, Serai SD, Pirasteh A, Bashir MR, Hamilton G, Hernando D, Hu HH, Hetterich H, Kühn JP, Kukuk GM, Loomba R, Middleton MS, Obuchowski NA, Song JS, Tang A, Wu X, Reeder SB, Sirlin CB, For the RSNA-QIBA PDFF Biomarker Committee. Linearity, Bias, and Precision of Hepatic Proton Density Fat Fraction Measurements by Using MR Imaging: A Meta-Analysis. Radiology 2018; 286:486-498. [PMID: 28892458 PMCID: PMC5813433 DOI: 10.1148/radiol.2017170550] [Citation(s) in RCA: 232] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Purpose To determine the linearity, bias, and precision of hepatic proton density fat fraction (PDFF) measurements by using magnetic resonance (MR) imaging across different field strengths, imager manufacturers, and reconstruction methods. Materials and Methods This meta-analysis was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic literature search identified studies that evaluated the linearity and/or bias of hepatic PDFF measurements by using MR imaging (hereafter, MR imaging-PDFF) against PDFF measurements by using colocalized MR spectroscopy (hereafter, MR spectroscopy-PDFF) or the precision of MR imaging-PDFF. The quality of each study was evaluated by using the Quality Assessment of Studies of Diagnostic Accuracy 2 tool. De-identified original data sets from the selected studies were pooled. Linearity was evaluated by using linear regression between MR imaging-PDFF and MR spectroscopy-PDFF measurements. Bias, defined as the mean difference between MR imaging-PDFF and MR spectroscopy-PDFF measurements, was evaluated by using Bland-Altman analysis. Precision, defined as the agreement between repeated MR imaging-PDFF measurements, was evaluated by using a linear mixed-effects model, with field strength, imager manufacturer, reconstruction method, and region of interest as random effects. Results Twenty-three studies (1679 participants) were selected for linearity and bias analyses and 11 studies (425 participants) were selected for precision analyses. MR imaging-PDFF was linear with MR spectroscopy-PDFF (R2 = 0.96). Regression slope (0.97; P < .001) and mean Bland-Altman bias (-0.13%; 95% limits of agreement: -3.95%, 3.40%) indicated minimal underestimation by using MR imaging-PDFF. MR imaging-PDFF was precise at the region-of-interest level, with repeatability and reproducibility coefficients of 2.99% and 4.12%, respectively. Field strength, imager manufacturer, and reconstruction method each had minimal effects on reproducibility. Conclusion MR imaging-PDFF has excellent linearity, bias, and precision across different field strengths, imager manufacturers, and reconstruction methods. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on October 2, 2017.
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12
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Schwimmer JB, Behling C, Angeles JE, Paiz M, Durelle J, Africa J, Newton KP, Brunt EM, Lavine JE, Abrams SH, Masand P, Krishnamurthy R, Wong K, Ehman RL, Yin M, Glaser KJ, Dzyubak B, Wolfson T, Gamst AC, Hooker J, Haufe W, Schlein A, Hamilton G, Middleton MS, Sirlin CB. Magnetic resonance elastography measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic fatty liver disease. Hepatology 2017; 66:1474-1485. [PMID: 28493388 PMCID: PMC5650504 DOI: 10.1002/hep.29241] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 03/23/2017] [Accepted: 04/24/2017] [Indexed: 12/14/2022]
Abstract
UNLABELLED 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 < 0.001). Overall cross-validated accuracy for detecting any fibrosis was 72.2% for all methods (95% confidence interval [CI], 61.8%-81.1%). Overall cross-validated accuracy for assessing advanced fibrosis was 88.9% (95% CI, 80.5%-94.5%) for center 1, 90.0% (95% CI, 81.9%-95.3%) for center 2, and 86.7% (95% CI, 77.9%-92.9%) for automated analysis. CONCLUSION 2D MRE can estimate hepatic stiffness in children with NAFLD. Further refinement and validation of automated analysis techniques will be an important step in standardizing MRE. How to best integrate MRE into clinical protocols for the assessment of NAFLD in children will require prospective evaluation. (Hepatology 2017;66:1474-1485).
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Affiliation(s)
- Jeffrey B. Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California,Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, California,Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Cynthia Behling
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Jorge Eduardo Angeles
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Melissa Paiz
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Janis Durelle
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Jonathan Africa
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Kimberly P. Newton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California,Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, California
| | - Elizabeth M. Brunt
- Department of Pathology and Immunology, Washington University, St. Louis, Missouri
| | | | - Stephanie H. Abrams
- Columbia University, New York, NY,Baylor College of Medicine, Houston, Texas,Houston Methodist Hospital, Houston, Texas
| | | | | | - Kelvin Wong
- Miller Children’s & Women’s Hospital Long Beach, California
| | | | - Meng Yin
- Mayo Clinic, Rochester, Minnesota
| | | | | | - Tanya Wolfson
- Computational and Applied Statistics Laboratory (CASL), San Diego Supercomputer Center, University of California, San Diego, California
| | - Anthony C. Gamst
- Computational and Applied Statistics Laboratory (CASL), San Diego Supercomputer Center, University of California, San Diego, California
| | - Jonathan Hooker
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - William Haufe
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Alexandra Schlein
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Gavin Hamilton
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Michael S. Middleton
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
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Bhat V, Velandai S, Belliappa V, Illayraja J, Halli KG, Gopalakrishnan G. Quantification of Liver Fat with mDIXON Magnetic Resonance Imaging, Comparison with the Computed Tomography and the Biopsy. J Clin Diagn Res 2017; 11:TC06-TC10. [PMID: 28892997 DOI: 10.7860/jcdr/2017/26317.10234] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 05/13/2017] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Accurate, non-invasive method of fat estimation is a valuable test for evaluation of diseases with abnormal hepatic fat. AIM To determine the accuracy of mDixon MR technique in assessment of liver fat over CT and to correlate the CT and MRI findings with biopsy. MATERIALS AND METHODS A prospective observational study was conducted at Imaging Services of Narayana Multispeciality Hospital between March 2011- December 2012. Thirty patients who attended the clinic for non-hepatic complaints were included in the study. Patients with known liver disease, cirrhosis, alcoholic liver disease, bleeding diathesis and claustrophobic patients were excluded from the study. Subjects underwent sonography, CT liver and MR examination of liver for fat estimation using mDixon protocol. Biopsy of the liver was performed either by image guidance or by direct biopsy. Liver Attenuation Index (LAI), fat estimation by MR methods were reviewed independently by two observers and compared with biopsy results. The statistical analysis was performed by SPSS. Pearson correlation was used to find the correlation between the left and right lobe of liver segments by CT and histological correlation. RESULTS There was good correlation between the MR estimation of liver fat and histological grading. Majority (90%) of patients had fat content of less than 10%. Maximal fat content of 28% was observed in one patient. LAI values poorly correlated with the MRI and histological observations. CONCLUSION MR estimation of the liver using mDixon technique yielded specific information about liver fat, correlated well with the histological grading. Technique is more accurate than CT, does not involve ionising radiation, hence recommended as method of choice.
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Affiliation(s)
- Venkatraman Bhat
- Senior Consultant, Department of Radiology, Narayana Health, Shaw Mazumdar Medical Center, Bengaluru, Karnataka, India
| | - Sundararaman Velandai
- Senior Scientist, Department of Medical Imaging, Philips Inovation Campus, Bengaluru, Karnataka, India
| | - Vikram Belliappa
- Senior Consultant, Department of Surgical Gastroenterology, Narayana Health, Shaw Mazumdar Medical Center, Bengaluru, Karnataka, India
| | - Jeyeram Illayraja
- Biostatistician, Department of Medical Research, Narayana Health, Bengaluru, Karnataka, India
| | - Karthik Gadabana Halli
- Consultant, Department of Radiology, Narayana Health, Shaw Mazumdar Medical Center, Bengaluru, Karnataka, India
| | - Gayathri Gopalakrishnan
- Senior Consultant, Department of Medical Gastroenterology, Narayana Health, Shaw Mazumdar Medical Center, Bengaluru, Karnataka, India
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14
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Zhou YJ, Zheng JN, Liu WY, Miele L, Vitale A, Van Poucke S, Zou TT, Fang DH, Shen S, Zhang DC, Zheng MH. The NAFL Risk Score: A simple scoring model to predict 4-y risk for non-alcoholic fatty liver. Clin Chim Acta 2017; 468:17-24. [PMID: 28111272 DOI: 10.1016/j.cca.2017.01.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 01/14/2017] [Accepted: 01/18/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND Although several risk factors for non-alcoholic fatty liver (NAFL) have been reported, there are few clinical scores that predict its incidence in the long term. We developed and validate a scoring model for individual prediction of 4-y risk for NAFL. METHODS Four-year follow-up data of 8226 initially NAFL-free subjects enrolled for an annual physical examination from Wenzhou Medical Center were analyzed. These subjects are randomly split into the training and the validation cohort. Univariate and multivariable logistic regression models were employed for model development. The selected variables were assigned an integer or half-integer risk score proportional to the estimated coefficient from the logistic model. Risk scores were tested in a validation cohort. We also compared the predictive performance of with that of the NAFLD Index by computing the area under the receiver operating characteristic curve (AUROC). RESULTS The NAFL Risk Score was developed as 0 to 18 points comprising of BMI, TG×GGT, ALT/AST, LDL-C/HDL-C and UA in both sexes. Comparison of the observed with the estimated incidence of NAFL at both cohorts showed satisfactory precision. In addition, the NAFL Risk Score showed relatively good discriminative power (AUROC=0.739 for males, 0.823 for females) compared with the NAFLD Index (AUROC=0.661 for males, 0.729 for females) in these Chinese subjects. CONCLUSIONS We developed and validated the NAFL Risk Score, a new scoring model to predict 4-y risk for NAFL. The NAFL Risk Score may be clinically simple and useful for assessing individual risk for NAFL.
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Affiliation(s)
- Yu-Jie Zhou
- Department of Hepatology, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ji-Na Zheng
- Department of Hepatology, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wen-Yue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Luca Miele
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Institute of Internal Medicine, Catholic University of Rome, Rome, Italy
| | | | - Sven Van Poucke
- Department of Anesthesiology, Critical Care, Emergency Medicine and Pain Therapy, Ziekenhuis Oost-Limburg, Genk, Belgium
| | - Tian-Tian Zou
- Department of Hepatology, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Dan-Hong Fang
- Department of Cardiovascular Medicine, The Heart Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Shengrong Shen
- Department of Food Science & Nutrition, Zhejiang University, Hangzhou, China
| | - Dong-Chu Zhang
- Wenzhou Medical Center, Wenzhou People's Hospital, Wenzhou, China
| | - Ming-Hua Zheng
- Department of Hepatology, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.
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15
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Schwimmer JB, Lavine JE, Wilson LA, Neuschwander-Tetri BA, Xanthakos SA, Kohli R, Barlow SE, Vos MB, Karpen SJ, Molleston JP, Whitington PF, Rosenthal P, Jain AK, Murray KF, Brunt EM, Kleiner DE, Van Natta ML, Clark JM, Tonascia J, Doo E. In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores. Gastroenterology 2016; 151:1141-1154.e9. [PMID: 27569726 PMCID: PMC5124386 DOI: 10.1053/j.gastro.2016.08.027] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 08/17/2016] [Accepted: 08/18/2016] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. METHODS We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis. RESULTS There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P = .005). CONCLUSIONS In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.
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Affiliation(s)
- Jeffrey B Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California; Department of Gastroenterology, Rady Children's Hospital, San Diego, California.
| | - Joel E Lavine
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University, and Morgan Stanley Children's Hospital of New York Presbyterian, New York, New York
| | - Laura A Wilson
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | | | - Stavra A Xanthakos
- Steatohepatitis Center, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Rohit Kohli
- Steatohepatitis Center, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Sarah E Barlow
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas
| | - Miriam B Vos
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia
| | - Saul J Karpen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia
| | - Jean P Molleston
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, Indiana
| | - Peter F Whitington
- Department of Pediatrics, Feinberg Medical School of Northwestern University and the Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Philip Rosenthal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Francisco Benioff Children's Hospital, San Francisco, California
| | - Ajay K Jain
- Department of Pediatrics, St. Louis University, St. Louis, Missouri
| | - Karen F Murray
- Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine and Seattle Children's, Seattle, Washington
| | - Elizabeth M Brunt
- Department of Pathology, Washington University in St. Louis, St. Louis, Missouri
| | | | - Mark L Van Natta
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Jeanne M Clark
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - James Tonascia
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Edward Doo
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
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The intrahepatic expression levels of bile acid transporters are inversely correlated with the histological progression of nonalcoholic fatty liver disease. J Gastroenterol 2016; 51:808-18. [PMID: 26601667 DOI: 10.1007/s00535-015-1148-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 11/10/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) presents as a spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter is progressive, and its pathogenesis remains poorly understood. Recently, bile acid (BA) metabolism has become a therapeutic focus in NASH patients. The aim of the present study was to explore changes in bile acid metabolism in NAFLD patients in the context of disease progression. METHODS We prospectively enrolled patients with clinically suspected NAFLD. Patients taking ursodeoxycholic acid were excluded. The intrahepatic expression levels of genes associated with BA metabolism were determined by quantitative PCR and immunohistochemistry. RESULTS Seventy-eight patients (male:female = 49:29) histologically diagnosed with NAFLD were analyzed. The expression levels of farnesoid X receptor, liver receptor homolog 1, and small heterodimer partner, key proteins in BA synthesis, significantly decreased as the NAFLD activity score (NAS) increased in either males or females. The levels of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme of BA synthesis, were not changed. Notably, the expression levels of a main export transporter, bile salt export pump (BSEP), significantly decreased as the NAS and the each NAS component increased in both genders. The decreases of BSEP levels were also observed by immunohistochemistry, particularly in areas with pronounced fatty changes in cases with high NAS. CONCLUSIONS The expression levels of the BA export transporter BSEP were inversely correlated with NAS in NAFLD patients. Such down-regulation may cause excessive BA levels in hepatocytes, leading to cell injury. Our findings may afford new insights into the pathogenesis of NASH.
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Fifty Years of Technological Innovation: Potential and Limitations of Current Technologies in Abdominal Magnetic Resonance Imaging and Computed Tomography. Invest Radiol 2016; 50:584-93. [PMID: 26039773 DOI: 10.1097/rli.0000000000000173] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Magnetic resonance imaging (MRI) has become an important modality for the diagnosis of intra-abdominal pathology. Hardware and pulse sequence developments have made it possible to derive not only morphologic but also functional information related to organ perfusion (dynamic contrast-enhanced MRI), oxygen saturation (blood oxygen level dependent), tissue cellularity (diffusion-weighted imaging), and tissue composition (spectroscopy). These techniques enable a more specific assessment of pathologic lesions and organ functionality. Magnetic resonance imaging has thus transitioned from a purely morphologic examination to a modality from which image-based disease biomarkers can be derived. This fits well with several emerging trends in radiology, such as the need to accurately assess response to costly treatment strategies and the need to improve lesion characterization to potentially avoid biopsy. Meanwhile, the cost-effectiveness, availability, and robustness of computed tomography (CT) ensure its place as the current workhorse for clinical imaging. Although the lower soft tissue contrast of CT relative to MRI is a long-standing limitation, other disadvantages such as ionizing radiation exposure have become a matter of public concern. Nevertheless, recent technical developments such as dual-energy CT or dynamic volume perfusion CT also provide more functional imaging beyond morphology.The aim of this article was to review and discuss the most important recent technical developments in abdominal MRI and state-of-the-art CT, with an eye toward the future, providing examples of their clinical utility for the evaluation of hepatic and renal pathologies.
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Zhang XX, Gu Q, Zhang L, Dai XS, Chen HP. Significance of plasma levels of adiponectin and leptin in elderly patients with colorectal adenomas and non-alcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2016; 24:1575-1580. [DOI: 10.11569/wcjd.v24.i10.1575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the clinical characters of colorectal adenomas in elder patients with non-alcoholic fatty liver disease (NAFLD), and to explore the relationship between adiponectin and leptin levels and colorectal adenomas which likely undergo malignant transformation.
METHODS: The information of past medical history and personal medical history were provided. Body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), lipoprotein a (Lpa), as well as position, size, number, and pathology of colorectal adenomas were detected and collected statistic between elderly patients with and without NAFLD. ELISA was used to detect plasma adiponectin and leptin levels.
RESULTS: More elderly patients with NAFLD had smoking history, diabetes mellitus, hypertension, hypertriglyceride, high LDL-C level and high BMI (P < 0.05) than in those without NAFLD. The numbers of colorectal adenomas (P < 0.05) and villous adenomas (P < 0.05) in patients with NAFLD were more than those in patients without NAFLD. Higher levels of adiponectin and lower levels of leptin were detected in patients with NAFLD, and in the villous adenomas group and high grade dysplasia group.
CONCLUSION: Adenomas in elderly patients with NAFLD have more chances to undergo malignant transformation than those in patients without NAFLD. The low expression of adiponectin and high expression of leptin may be one of the possible mechanisms.
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Tang A, Chen J, Le TA, Changchien C, Hamilton G, Middleton MS, Loomba R, Sirlin CB. Cross-sectional and longitudinal evaluation of liver volume and total liver fat burden in adults with nonalcoholic steatohepatitis. ACTA ACUST UNITED AC 2015; 40:26-37. [PMID: 25015398 DOI: 10.1007/s00261-014-0175-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE To explore the cross-sectional and longitudinal relationships between fractional liver fat content, liver volume, and total liver fat burden. METHODS In 43 adults with non-alcoholic steatohepatitis participating in a clinical trial, liver volume was estimated by segmentation of magnitude-based low-flip-angle multiecho GRE images. The liver mean proton density fat fraction (PDFF) was calculated. The total liver fat index (TLFI) was estimated as the product of liver mean PDFF and liver volume. Linear regression analyses were performed. RESULTS Cross-sectional analyses revealed statistically significant relationships between TLFI and liver mean PDFF (R 2 = 0.740 baseline/0.791 follow-up, P < 0.001 baseline/P < 0.001 follow-up), and between TLFI and liver volume (R 2 = 0.352/0.452, P < 0.001/< 0.001). Longitudinal analyses revealed statistically significant relationships between liver volume change and liver mean PDFF change (R 2 = 0.556, P < 0.001), between TLFI change and liver mean PDFF change (R 2 = 0.920, P < 0.001), and between TLFI change and liver volume change (R 2 = 0.735, P < 0.001). CONCLUSION Liver segmentation in combination with MRI-based PDFF estimation may be used to monitor liver volume, liver mean PDFF, and TLFI in a clinical trial.
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Quantification of hepatic steatosis with a multistep adaptive fitting MRI approach: prospective validation against MR spectroscopy. AJR Am J Roentgenol 2015; 204:297-306. [PMID: 25615751 DOI: 10.2214/ajr.14.12457] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE. The purpose of this study is to prospectively compare hybrid and complex chemical shift-based MRI fat quantification methods against MR spectroscopy (MRS) for the measurement of hepatic steatosis. SUBJECTS AND METHODS. Forty-two subjects (18 men and 24 women; mean ± SD age, 52.8 ± 14 years) were prospectively enrolled and imaged at 3 T with a chemical shift-based MRI sequence and a single-voxel MRS sequence, each in one breath-hold. Proton density fat fraction and rate constant (R2*) using both single- and dual-R2* hybrid fitting methods, as well as proton density fat fraction and R2* maps using a complex fitting method, were generated. A single radiologist colocalized volumes of interest on the proton density fat fraction and R2* maps according to the spectroscopy measurement voxel. Agreement among the three MRI methods and the MRS proton density fat fraction values was assessed using linear regression, intraclass correlation coefficient (ICC), and Bland-Altman analysis. RESULTS. Correlation between the MRI and MRS measures of proton density fat fraction was excellent. Linear regression coefficients ranged from 0.98 to 1.01, and intercepts ranged from -1.12% to 0.49%. Agreement measured by ICC was also excellent (0.99 for all three methods). Bland-Altman analysis showed excellent agreement, with mean differences of -1.0% to 0.6% (SD, 1.3-1.6%). CONCLUSION. The described MRI-based liver proton density fat fraction measures are clinically feasible and accurate. The validation of proton density fat fraction quantification methods is an important step toward wide availability and acceptance of the MRI-based measurement of proton density fat fraction as an accurate and generalizable biomarker.
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21
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Schwimmer JB, Middleton MS, Behling C, Newton KP, Awai HI, Paiz MN, Lam J, Hooker JC, Hamilton G, Fontanesi J, Sirlin CB. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology 2015; 61:1887-95. [PMID: 25529941 PMCID: PMC4670559 DOI: 10.1002/hep.27666] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 12/13/2014] [Indexed: 12/12/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. In order to advance the field of NAFLD, noninvasive imaging methods for measuring liver fat are needed. Advanced magnetic resonance imaging (MRI) has shown great promise for the quantitative assessment of hepatic steatosis but has not been validated in children. Therefore, this study was designed to evaluate the correlation and diagnostic accuracy of MRI-estimated liver proton density fat fraction (PDFF), a biomarker for hepatic steatosis, compared to histologic steatosis grade in children. The study included 174 children with a mean age of 14.0 years. Liver PDFF estimated by MRI was significantly (P < 0.01) correlated (0.725) with steatosis grade. The correlation of MRI-estimated liver PDFF and steatosis grade was influenced by both sex and fibrosis stage. The correlation was significantly (P < 0.01) stronger in girls (0.86) than in boys (0.70). The correlation was significantly (P < 0.01) weaker in children with stage 2-4 fibrosis (0.61) than children with no fibrosis (0.76) or stage 1 fibrosis (0.78). The diagnostic accuracy of commonly used threshold values to distinguish between no steatosis and mild steatosis ranged from 0.69 to 0.82. The overall accuracy of predicting the histologic steatosis grade from MRI-estimated liver PDFF was 56%. No single threshold had sufficient sensitivity and specificity to be considered diagnostic for an individual child. CONCLUSIONS Advanced magnitude-based MRI can be used to estimate liver PDFF in children, and those PDFF values correlate well with steatosis grade by liver histology. Thus, magnitude-based MRI has the potential for clinical utility in the evaluation of NAFLD, but at this time no single threshold value has sufficient accuracy to be considered diagnostic for an individual child.
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Affiliation(s)
- Jeffrey B. Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California,Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, California,Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Michael S. Middleton
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Cynthia Behling
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California,Department of Pathology, Sharp Medical Center, San Diego, California
| | - Kimberly P. Newton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California,Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, California
| | - Hannah I. Awai
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California,Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, California,Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Melissa N. Paiz
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California
| | - Jessica Lam
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California,School of Medicine, Loma Linda University, Loma Linda, California
| | - Jonathan C. Hooker
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - Gavin Hamilton
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
| | - John Fontanesi
- Center for Management Science in Health, Division of General Internal Medicine, Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California,Department of Family and Preventive Medicine, University of California, San Diego School of Medicine, La Jolla, California,Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, California
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22
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Lake AD, Novak P, Shipkova P, Aranibar N, Robertson DG, Reily MD, Lehman-McKeeman LD, Vaillancourt RR, Cherrington NJ. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids 2015; 47:603-15. [PMID: 25534430 PMCID: PMC4329055 DOI: 10.1007/s00726-014-1894-9] [Citation(s) in RCA: 171] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 12/03/2014] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127% of normal), isoleucine (139%), and valine (147%) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients.
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Affiliation(s)
- April D. Lake
- Department of Pharmacology and Toxicology, The University of Arizona, 1703 East Mabel St, PO Box 210207, Tucson, AZ 85721, USA
| | - Petr Novak
- Biology Centre ASCR, Institute of Plant Molecular Biology, České Budějovice, Czech Republic
| | - Petia Shipkova
- Bristol-Myers Squibb Co, Pharmaceutical Candidate Optimization, Princeton, NJ, USA
| | - Nelly Aranibar
- Bristol-Myers Squibb Co, Pharmaceutical Candidate Optimization, Princeton, NJ, USA
| | - Donald G. Robertson
- Bristol-Myers Squibb Co, Pharmaceutical Candidate Optimization, Princeton, NJ, USA
| | - Michael D. Reily
- Bristol-Myers Squibb Co, Pharmaceutical Candidate Optimization, Princeton, NJ, USA
| | | | - Richard R. Vaillancourt
- Department of Pharmacology and Toxicology, The University of Arizona, 1703 East Mabel St, PO Box 210207, Tucson, AZ 85721, USA
| | - Nathan J. Cherrington
- Department of Pharmacology and Toxicology, The University of Arizona, 1703 East Mabel St, PO Box 210207, Tucson, AZ 85721, USA
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23
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Okushin K, Takahashi Y, Yamamichi N, Shimamoto T, Enooku K, Fujinaga H, Tsutsumi T, Shintani Y, Sakaguchi Y, Ono S, Kodashima S, Fujishiro M, Moriya K, Yotsuyanagi H, Mitsushima T, Koike K. Helicobacter pylori infection is not associated with fatty liver disease including non-alcoholic fatty liver disease: a large-scale cross-sectional study in Japan. BMC Gastroenterol 2015; 15:25. [PMID: 25880912 PMCID: PMC4349671 DOI: 10.1186/s12876-015-0247-9] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 02/02/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Fatty liver disease (FLD) including non-alcoholic fatty liver disease (NAFLD), a rapidly emerging and widely recognized liver disease today, is regarded as a hepatic manifestation of metabolic syndrome. Helicobacter pylori, one of the most common pathogens worldwide, has been reported to be associated with metabolic syndrome, but whether there is a direct association with FLD is as of yet unclear. The aim of this study was to clarify the association of FLD and NAFLD with causative background factors including Helicobacter pylori infection. METHODS This was a cross-sectional study of Japanese adults who received medical checkups at a single medical center in 2010.Univariate and multivariate statistical analysis was performed to evaluate background factors for ultrasonography diagnosed FLD. Subjects free from alcohol influence were similarly analyzed for NAFLD. RESULTS Of a total of 13,737 subjects, FLD was detected in 1,456 of 6,318 females (23.0 %) and 3,498 of 7,419 males (47.1%). Multivariable analyses revealed that body mass index (standardized coefficients of females and males (β-F/M) =143.5/102.5), serum ALT (β-F/M = 25.8/75.7), age (β-F/M = 34.3/17.2), and platelet count (β-F/M = 17.8/15.2) were positively associated with FLD in both genders. Of the 5,289 subjects free from alcohol influence, NAFLD was detected in 881 of 3,473 females (25.4%) and 921 of 1,816 males (50.7%). Body mass index (β-F/M = 113.3/55.3), serum ALT (β-F/M = 21.6/53.8), and platelet count (β-F/M = 13.8/11.8) were positively associated with NAFLD in both genders. Metabolic syndrome was positively associated with FLD and NAFLD only in males. In contrast, Helicobacter pylori infection status was neither associated with FLD nor NAFLD regardless of gender. CONCLUSIONS Body mass index, serum ALT and platelet count were significantly associated with FLD and NAFLD, whereas infection of Helicobacter pylori was not.
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Affiliation(s)
- Kazuya Okushin
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Yu Takahashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Takeshi Shimamoto
- Kameda Medical Center Makuhari (CD-2, 1-3, Nakase, Mihama-ku, Chiba-city, Japan.
| | - Kenichiro Enooku
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hidetaka Fujinaga
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Takeya Tsutsumi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Yoshizumi Shintani
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Yoshiki Sakaguchi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Satoshi Ono
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Shinya Kodashima
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Kyoji Moriya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hiroshi Yotsuyanagi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Toru Mitsushima
- Kameda Medical Center Makuhari (CD-2, 1-3, Nakase, Mihama-ku, Chiba-city, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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24
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Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, Valasek M, Lin G, Brenner D, Gamst A, Ehman R, Sirlin C. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology 2014; 60:1920-8. [PMID: 25103310 PMCID: PMC4245360 DOI: 10.1002/hep.27362] [Citation(s) in RCA: 384] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023]
Abstract
UNLABELLED Retrospective studies have shown that two-dimensional magnetic resonance elastography (2D-MRE), a novel MR method for assessment of liver stiffness, correlates with advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Prospective data on diagnostic accuracy of 2D-MRE in the detection of advanced fibrosis in NAFLD are needed. The aim of this study is to prospectively assess the diagnostic accuracy of 2D-MRE, a noninvasive imaging biomarker, in predicting advanced fibrosis (stage 3 or 4) in well-characterized patients with biopsy-proven NAFLD. This is a cross-sectional analysis of a prospective study including 117 consecutive patients (56% women) with biopsy-proven NAFLD who underwent a standardized research visit: history, exam, liver biopsy assessment (using the nonalcoholic steatohepatitis Clinical Research Network histological scoring system), and 2D-MRE from 2011 to 2013. The radiologist and pathologist were blinded to clinical and pathology/imaging data, respectively. Receiver operating characteristics (ROCs) were examined to assess the diagnostic test performance of 2D-MRE in predicting advanced fibrosis. The mean (± standard deviation) of age and body mass index was 50.1 (± 13.4) years and 32.4 (± 5.0) kg/m(2), respectively. The median time interval between biopsy and 2D-MRE was 45 days (interquartile range: 50 days). The number of patients with fibrosis stages 0, 1, 2, 3, and 4 was 43, 39, 13, 12, and 10, respectively. The area under the ROC curve for 2D-MRE discriminating advanced fibrosis (stage 3-4) from stage 0-2 fibrosis was 0.924 (P < 0.0001). A threshold of >3.63 kPa had a sensitivity of 0.86 (95% confidence interval [CI]: 0.65-0.97), specificity of 0.91 (95% CI: 0.83-0.96), positive predictive value of 0.68 (95% CI: 0.48-0.84), and negative predictive value of 0.97 (95% CI: 0.91-0.99). CONCLUSIONS MRE is accurate in predicting advanced fibrosis and may be utilized for noninvasive diagnosis of advanced fibrosis in patients with NAFLD.
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Affiliation(s)
- Rohit Loomba
- Division of Gastroenterology, University of California at San DiegoLa Jolla, CA,NAFLD Translational Research Unit, Department of Medicine, University of California at San DiegoLa Jolla, CA,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San DiegoLa Jolla, CA,* These authors contributed equally to this work
| | - Tanya Wolfson
- Departments of Mathematics, University of California at San DiegoLa Jolla, CA
| | - Brandon Ang
- NAFLD Translational Research Unit, Department of Medicine, University of California at San DiegoLa Jolla, CA
| | - Jonathan Hooker
- Liver Imaging Group, Department of Radiology, University of California at San DiegoLa Jolla, CA,** Correction added after publication October 29, 2014: Author name Jonathan Booker was changed to Jonathan Hooker
| | | | | | - Mark Valasek
- Pathology, University of California at San DiegoLa Jolla, CA
| | - Grace Lin
- Pathology, University of California at San DiegoLa Jolla, CA
| | - David Brenner
- Division of Gastroenterology, University of California at San DiegoLa Jolla, CA
| | - Anthony Gamst
- Departments of Mathematics, University of California at San DiegoLa Jolla, CA
| | | | - Claude Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San DiegoLa Jolla, CA,* These authors contributed equally to this work
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25
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Tang A, Desai A, Hamilton G, Wolfson T, Gamst A, Lam J, Clark L, Hooker J, Chavez T, Ang BD, Middleton MS, Peterson M, Loomba R, Sirlin CB. Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease. Radiology 2014; 274:416-25. [PMID: 25247408 DOI: 10.1148/radiol.14140754] [Citation(s) in RCA: 245] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE To evaluate the diagnostic performance of previously proposed high-specificity magnetic resonance (MR) imaging-estimated proton density fat fraction (PDFF) thresholds for diagnosis of steatosis grade 1 or higher (PDFF threshold of 6.4%), grade 2 or higher (PDFF threshold of 17.4%), and grade 3 (PDFF threshold of 22.1%) by using histologic findings as a reference in an independent cohort of adults known to have or suspected of having nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS This prospective, cross-sectional, institutional review board-approved, HIPAA-compliant single-center study was conducted in an independent cohort of 89 adults known to have or suspected of having NAFLD who underwent contemporaneous liver biopsy. MR imaging PDFF was estimated at 3 T by using magnitude-based low-flip-angle multiecho gradient-recalled-echo imaging with T2* correction and multipeak modeling. Steatosis was graded histologically (grades 0, 1, 2, and 3, according to the Nonalcoholic Steatohepatitis Clinical Research Network scoring system). Sensitivity, specificity, and binomial confidence intervals were calculated for the proposed MR imaging PDFF thresholds. RESULTS The proposed MR imaging PDFF threshold of 6.4% to diagnose grade 1 or higher steatosis had 86% sensitivity (71 of 83 patients; 95% confidence interval [CI]: 76, 92) and 83% specificity (five of six patients; 95% CI: 36, 100). The threshold of 17.4% to diagnose grade 2 or higher steatosis had 64% sensitivity (28 of 44 patients; 95% CI: 48, 78) and 96% specificity (43 of 45 patients; 95% CI: 85, 100). The threshold of 22.1% to diagnose grade 3 steatosis had 71% sensitivity (10 of 14 patients; 95% CI: 42, 92) and 92% specificity (69 of 75 patients; 95% CI: 83, 97). CONCLUSION In an independent cohort of adults known to have or suspected of having NAFLD, the previously proposed MR imaging PDFF thresholds provided moderate to high sensitivity and high specificity for diagnosis of grade 1 or higher, grade 2 or higher, and grade 3 steatosis. Prospective multicenter studies are now needed to further validate these high-specificity thresholds.
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Affiliation(s)
- An Tang
- From the Liver Imaging Group, Department of Radiology (A.T., A.D., G.H., J.L., L.C., J.H., T.C., M.S.M., C.B.S.), Computational and Applied Statistics Laboratory, San Diego Supercomputer Center (T.W., A.G.), Department of Pathology (M.P.), and Department of Medicine, Division of Gastroenterology (B.D.A., R.L.), University of California San Diego, 408 Dickinson St, San Diego, CA 92103-8226
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Rehm JL, Connor EL, Wolfgram P, Eickhoff JC, Reeder SB, Allen DB. Predicting hepatic steatosis in a racially and ethnically diverse cohort of adolescent girls. J Pediatr 2014; 165:319-325.e1. [PMID: 24857521 PMCID: PMC4131842 DOI: 10.1016/j.jpeds.2014.04.019] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 02/17/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To develop a risk assessment model for early detection of hepatic steatosis using common anthropometric and metabolic markers. STUDY DESIGN This was a cross-sectional study of 134 adolescent and young adult females, age 11-22 years (mean 13.3±2 years) from a middle school and clinics in Madison, Wisconsin. The ethnic distribution was 27% Hispanic and 73% non-Hispanic; the racial distribution was 64% Caucasian, 31% African-American, and 5% Asian, Fasting glucose, fasting insulin, alanine aminotransferase (ALT), body mass index (BMI), waist circumference (WC), and other metabolic markers were assessed. Hepatic fat was quantified using magnetic resonance imaging proton density fat fraction (MR-PDFF). Hepatic steatosis was defined as MR-PDFF>5.5%. Outcome measures were sensitivity, specificity, and positive predictive value (PPV) of BMI, WC, ALT, fasting insulin, and ethnicity as predictors of hepatic steatosis, individually and combined, in a risk assessment model. Classification and regression tree methodology was used to construct a decision tree for predicting hepatic steatosis. RESULTS MR-PDFF revealed hepatic steatosis in 16% of subjects (27% overweight, 3% nonoverweight). Hispanic ethnicity conferred an OR of 4.26 (95% CI, 1.65-11.04; P=.003) for hepatic steatosis. BMI and ALT did not independently predict hepatic steatosis. A BMI>85% combined with ALT>65 U/L had 9% sensitivity, 100% specificity, and 100% PPV. Lowering the ALT value to 24 U/L increased the sensitivity to 68%, but reduced the PPV to 47%. A risk assessment model incorporating fasting insulin, total cholesterol, WC, and ethnicity increased sensitivity to 64%, specificity to 99% and PPV to 93%. CONCLUSION A risk assessment model can increase specificity, sensitivity, and PPV for identifying the risk of hepatic steatosis and guide the efficient use of biopsy or imaging for early detection and intervention.
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Affiliation(s)
- Jennifer L Rehm
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
| | - Ellen L Connor
- Pediatrics, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States
| | - Peter Wolfgram
- Medical College of Wisconsin, Milwaukee, WI, United States
| | - Jens C Eickhoff
- Biostatistics and Medical Informatics, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States
| | - Scott B Reeder
- Radiology, Medical Physics, Biomedical Engineering, Medicine, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States
| | - David B Allen
- Pediatrics, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States
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27
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Automated patient-tailored screening of the liver for diffuse steatosis and iron overload using MRI. AJR Am J Roentgenol 2013; 201:583-8. [PMID: 23971450 DOI: 10.2214/ajr.12.10051] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The purpose of this article is to validate an automated screening method for evaluation of hepatic steatosis or siderosis. MATERIALS AND METHODS This was a two-part study, with retrospective and prospective portions. First, 130 consecutive abdominal MRI examinations, including both the automated algorithm and reference standard fat and iron quantification, were retrospectively identified. The algorithm's performance was validated against the reference standard and was compared with the performance of three expert readers. Subsequently, 39 subjects undergoing liver MRI were prospectively identified and enrolled. These subjects were scanned with a protocol where quantification sequences were either performed or not performed on the basis of the recommendation of the algorithm. Total examination time in these subjects was compared with examination times in the 90 subjects from the retrospective cohort who had undergone a similar liver MRI protocol with complete quantification. RESULTS The automated algorithm was accurate in determining the presence of deposition disease (93.1%), with no significant difference between its conclusions and those of any of the readers (p=0.48-1.0). Use of the algorithm resulted in a small but statistically significant time savings compared with performing quantification in all subjects (28 minutes 56 seconds vs 31 minutes 20 seconds; p<0.05). CONCLUSION Automated screening for hepatic steatosis and siderosis can be performed in real time during abdominal MRI examinations, can save total scan time compared with always performing quantification, and could serve as a gatekeeper for dedicated quantification sequences.
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28
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Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Compr Physiol 2013; 2:1143-211. [PMID: 23798298 DOI: 10.1002/cphy.c110025] [Citation(s) in RCA: 1365] [Impact Index Per Article: 113.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Chronic diseases are major killers in the modern era. Physical inactivity is a primary cause of most chronic diseases. The initial third of the article considers: activity and prevention definitions; historical evidence showing physical inactivity is detrimental to health and normal organ functional capacities; cause versus treatment; physical activity and inactivity mechanisms differ; gene-environment interaction (including aerobic training adaptations, personalized medicine, and co-twin physical activity); and specificity of adaptations to type of training. Next, physical activity/exercise is examined as primary prevention against 35 chronic conditions [accelerated biological aging/premature death, low cardiorespiratory fitness (VO2max), sarcopenia, metabolic syndrome, obesity, insulin resistance, prediabetes, type 2 diabetes, nonalcoholic fatty liver disease, coronary heart disease, peripheral artery disease, hypertension, stroke, congestive heart failure, endothelial dysfunction, arterial dyslipidemia, hemostasis, deep vein thrombosis, cognitive dysfunction, depression and anxiety, osteoporosis, osteoarthritis, balance, bone fracture/falls, rheumatoid arthritis, colon cancer, breast cancer, endometrial cancer, gestational diabetes, pre-eclampsia, polycystic ovary syndrome, erectile dysfunction, pain, diverticulitis, constipation, and gallbladder diseases]. The article ends with consideration of deterioration of risk factors in longer-term sedentary groups; clinical consequences of inactive childhood/adolescence; and public policy. In summary, the body rapidly maladapts to insufficient physical activity, and if continued, results in substantial decreases in both total and quality years of life. Taken together, conclusive evidence exists that physical inactivity is one important cause of most chronic diseases. In addition, physical activity primarily prevents, or delays, chronic diseases, implying that chronic disease need not be an inevitable outcome during life.
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Affiliation(s)
- Frank W Booth
- Departments of Biomedical Sciences, Medical Pharmacology and Physiology, and Nutrition and Exercise Physiology, Dalton Cardiovascular Institute, University of Missouri, Columbia, Missouri, USA.
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Schwimmer JB, Newton KP, Awai HI, Choi LJ, Garcia MA, Ellis LL, Vanderwall K, Fontanesi J. Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013; 38:1267-77. [PMID: 24117728 PMCID: PMC3984047 DOI: 10.1111/apt.12518] [Citation(s) in RCA: 158] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 09/06/2013] [Accepted: 09/13/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Screening overweight and obese children for non-alcoholic fatty liver disease (NAFLD) is recommended by paediatric and endocrinology societies. However, gastroenterology societies have called for more data before making a formal recommendation. AIM To determine whether the detection of suspected NAFLD in overweight and obese children through screening in primary care and referral to paediatric gastroenterology resulted in a correct diagnosis of NAFLD. METHODS Information generated in the clinical evaluation of 347 children identified with suspected NAFLD through screening in primary care and referral to paediatric gastroenterology was captured prospectively. Diagnostic outcomes were reported. The diagnostic performance of two times the upper limit of normal (ULN) for alanine aminotransferase (ALT) was assessed. RESULTS Non-alcoholic fatty liver disease was diagnosed in 55% of children identified by screening and referral. Liver disease other than NAFLD was present in 18% of those referred. Autoimmune hepatitis was the most common alternative diagnosis. Children with NAFLD had significantly (P < 0.05) higher screening ALT (98 ± 95) than children with liver disease other than NAFLD (86 ± 74). Advanced fibrosis was present in 11% of children. For the diagnosis of NAFLD, screening ALT two times the clinical ULN had a sensitivity of 57% and a specificity of 71%. CONCLUSIONS Screening of overweight and obese children in primary care for NAFLD with referral to paediatric gastroenterology has the potential to identify clinically relevant liver pathology. Consensus is needed on how to value the risk and rewards of screening and referral, to identify children with liver disease in the most appropriate manner.
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Affiliation(s)
- J B Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, San Diego School of Medicine, University of CaliforniaSan Diego, CA, USA,Department of Gastroenterology, Rady Children's Hospital San DiegoSan Diego, CA, USA,Liver Imaging Group, Department of Radiology, San Diego School of Medicine, University of CaliforniaSan Diego, CA, USA
| | - K P Newton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, San Diego School of Medicine, University of CaliforniaSan Diego, CA, USA,Department of Gastroenterology, Rady Children's Hospital San DiegoSan Diego, CA, USA
| | - H I Awai
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, San Diego School of Medicine, University of CaliforniaSan Diego, CA, USA,Department of Gastroenterology, Rady Children's Hospital San DiegoSan Diego, CA, USA,Liver Imaging Group, Department of Radiology, San Diego School of Medicine, University of CaliforniaSan Diego, CA, USA
| | - L J Choi
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, San Diego School of Medicine, University of CaliforniaSan Diego, CA, USA,Department of Gastroenterology, Rady Children's Hospital San DiegoSan Diego, CA, USA
| | - M A Garcia
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, San Diego School of Medicine, University of CaliforniaSan Diego, CA, USA,Department of Gastroenterology, Rady Children's Hospital San DiegoSan Diego, CA, USA
| | - L L Ellis
- Department of Pathology, Rady Children's Hospital San DiegoSan Diego, CA, USA,Department of Pathology, San Diego School of Medicine, University of CaliforniaLa Jolla, CA, USA,Department of Medical Sciences, Frank H. Netter MD School of Medicine at Quinnipiac UniversityHamden, CT, USA
| | - K Vanderwall
- Department of Anesthesiology, Rady Children's Hospital San DiegoSan Diego, CA, USA
| | - J Fontanesi
- Division of General Internal Medicine, Department of Medicine, Center for Management Science in Health, San Diego School of Medicine, University of CaliforniaLa Jolla, CA, USA,Departments of Family and Preventive Medicine and Pediatrics, San Diego School of Medicine, University of CaliforniaLa Jolla, CA, USA
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Hardwick RN, Ferreira DW, More VR, Lake AD, Lu Z, Manautou JE, Slitt AL, Cherrington NJ. Altered UDP-glucuronosyltransferase and sulfotransferase expression and function during progressive stages of human nonalcoholic fatty liver disease. Drug Metab Dispos 2013; 41:554-61. [PMID: 23223517 PMCID: PMC3583487 DOI: 10.1124/dmd.112.048439] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 12/07/2012] [Indexed: 12/25/2022] Open
Abstract
The UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) represent major phase II drug-metabolizing enzymes that are also responsible for maintaining cellular homeostasis by metabolism of several endogenous molecules. Perturbations in the expression or function of these enzymes can lead to metabolic disorders and improper management of xenobiotics and endobiotics. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Because the liver plays a central role in the metabolism of xenobiotics, the purpose of the current study was to determine the effect of human NAFLD progression on the expression and function of UGTs and SULTs in normal, steatosis, NASH (fatty), and NASH (not fatty/cirrhosis) samples. We identified upregulation of UGT1A9, 2B10, and 3A1 and SULT1C4 mRNA in both stages of NASH, whereas UGT2A3, 2B15, and 2B28 and SULT1A1, 2B1, and 4A1 as well as 3'-phosphoadenosine-5'-phosphosulfate synthase 1 were increased in NASH (not fatty/cirrhosis) only. UGT1A9 and 1A6 and SULT1A1 and 2A1 protein levels were decreased in NASH; however, SULT1C4 was increased. Measurement of the glucuronidation and sulfonation of acetaminophen (APAP) revealed no alterations in glucuronidation; however, SULT activity was increased in steatosis compared with normal samples, but then decreased in NASH compared with steatosis. In conclusion, the expression of specific UGT and SULT isoforms appears to be differentially regulated, whereas sulfonation of APAP is disrupted during progression of NAFLD.
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Affiliation(s)
- Rhiannon N Hardwick
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel, Tucson, AZ 85721, USA
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31
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Barsalani R, Riesco E, Lavoie JM, Dionne IJ. Effect of exercise training and isoflavones on hepatic steatosis in overweight postmenopausal women. Climacteric 2013; 16:88-95. [PMID: 22530610 DOI: 10.3109/13697137.2012.662251] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Postmenopausal women are particularly inclined to an increased risk of developing non-alcoholic hepatic steatosis. The purpose of this study was to investigate whether adding isoflavone supplementation to exercise training could reduce the risk. METHODS In a 6-month, double-blind, randomized, controlled trial, 54 healthy overweight-to-obese (body mass index 28-40 kg/m2) postmenopausal women were randomly assigned to one of the following groups: (1) exercise and isoflavones (Ex-Iso; n = 26), (2) exercise and placebo (Ex-Pla; n = 28). Exercise training consisted of three weekly sessions of mixed training. We examined the plasma level of specific hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, and alkaline phosphatase) as a reflection of fatty liver along with the calculation of the fatty liver index. All measures were obtained at baseline and after the 6-month intervention. RESULTS Following the intervention, a lower fatty liver index (p <0.01; 29% in Ex-Iso, 18% in Ex-Pla) and plasma γ-glutamyltransferase (p <0.01; 22% in Ex-Iso, 16% in Ex-Pla) were observed in both groups, with a higher reduction in the Ex-Iso group. On the other hand, for all other hepatic enzymes, there was no change. CONCLUSIONS Our results show that exercise training appears to bring favorable changes in the plasma level of hepatic enzymes, possibly due to the lowering of liver fat content. While postmenopausal women can benefit from this intervention to decrease the risk of developing non-alcoholic hepatic steatosis, it seems that the addition of isoflavones to exercise training provides some additional effects to those provided by exercise alone.
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Affiliation(s)
- R Barsalani
- Faculty of Physical Education and Sports, University of Sherbrooke, Sherbrooke, Québec
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Jiang ZG, Robson SC, Yao Z. Lipoprotein metabolism in nonalcoholic fatty liver disease. J Biomed Res 2012; 27:1-13. [PMID: 23554788 PMCID: PMC3596749 DOI: 10.7555/jbr.27.20120077] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Revised: 08/23/2012] [Accepted: 08/29/2012] [Indexed: 12/18/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), an escalating health problem worldwide, covers a spectrum of pathologies characterized by fatty accumulation in hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellular role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metabolism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD.
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Affiliation(s)
- Zhenghui Gordon Jiang
- Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
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Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative Assessment of Liver Fat with Magnetic Resonance Imaging and Spectroscopy. J Magn Reson Imaging 2011; 34:729-749. [PMID: 22025886 PMCID: PMC3177109 DOI: 10.1002/jmri.22775] [Citation(s) in RCA: 247] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Hepatic steatosis is characterized by abnormal and excessive accumulation of lipids within hepatocytes. It is an important feature of diffuse liver disease, and the histological hallmark of non-alcoholic fatty liver disease (NAFLD). Other conditions associated with steatosis include alcoholic liver disease, viral hepatitis, HIV and genetic lipodystrophies, cystic fibrosis liver disease, and hepatotoxicity from various therapeutic agents. Liver biopsy, the current clinical gold standard for assessment of liver fat, is invasive and has sampling errors, and is not optimal for screening, monitoring, clinical decision making, or well-suited for many types of research studies. Non-invasive methods that accurately and objectively quantify liver fat are needed. Ultrasound (US) and computed tomography (CT) can be used to assess liver fat but have limited accuracy as well as other limitations. Magnetic resonance (MR) techniques can decompose the liver signal into its fat and water signal components and therefore assess liver fat more directly than CT or US. Most magnetic resonance (MR) techniques measure the signal fat-fraction (the fraction of the liver MR signal attributable to liver fat), which may be confounded by numerous technical and biological factors and may not reliably reflect fat content. By addressing the factors that confound the signal fat-fraction, advanced MR techniques measure the proton density fat-fraction (the fraction of the liver proton density attributable to liver fat), which is a fundamental tissue property and a direct measure of liver fat content. These advanced techniques show promise for accurate fat quantification and are likely to be commercially available soon.
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Affiliation(s)
- Scott B. Reeder
- Liver Imaging Research Group, Departments of Radiology, Medical Physics, Biomedical Engineering and Medicine, University of Wisconsin, Madison, WI
| | - Irene Cruite
- Liver Imaging Group, Department of Radiology, University of California San Diego, CA
| | - Gavin Hamilton
- Liver Imaging Group, Department of Radiology, University of California San Diego, CA
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California San Diego, CA
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Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative Assessment of Liver Fat with Magnetic Resonance Imaging and Spectroscopy. J Magn Reson Imaging 2011. [PMID: 22025886 DOI: 10.1002/jmri.22580] [Citation(s) in RCA: 538] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic steatosis is characterized by abnormal and excessive accumulation of lipids within hepatocytes. It is an important feature of diffuse liver disease, and the histological hallmark of non-alcoholic fatty liver disease (NAFLD). Other conditions associated with steatosis include alcoholic liver disease, viral hepatitis, HIV and genetic lipodystrophies, cystic fibrosis liver disease, and hepatotoxicity from various therapeutic agents. Liver biopsy, the current clinical gold standard for assessment of liver fat, is invasive and has sampling errors, and is not optimal for screening, monitoring, clinical decision making, or well-suited for many types of research studies. Non-invasive methods that accurately and objectively quantify liver fat are needed. Ultrasound (US) and computed tomography (CT) can be used to assess liver fat but have limited accuracy as well as other limitations. Magnetic resonance (MR) techniques can decompose the liver signal into its fat and water signal components and therefore assess liver fat more directly than CT or US. Most magnetic resonance (MR) techniques measure the signal fat-fraction (the fraction of the liver MR signal attributable to liver fat), which may be confounded by numerous technical and biological factors and may not reliably reflect fat content. By addressing the factors that confound the signal fat-fraction, advanced MR techniques measure the proton density fat-fraction (the fraction of the liver proton density attributable to liver fat), which is a fundamental tissue property and a direct measure of liver fat content. These advanced techniques show promise for accurate fat quantification and are likely to be commercially available soon.
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Affiliation(s)
- Scott B Reeder
- Liver Imaging Research Group, Departments of Radiology, Medical Physics, Biomedical Engineering and Medicine, University of Wisconsin, Madison, WI
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35
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Exercise and Omega-3 Polyunsaturated Fatty Acid Supplementation for the Treatment of Hepatic Steatosis in Hyperphagic OLETF Rats. J Nutr Metab 2011; 2012:268680. [PMID: 21918718 PMCID: PMC3171760 DOI: 10.1155/2012/268680] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Accepted: 07/11/2011] [Indexed: 12/13/2022] Open
Abstract
Background and Aims. This study examined if exercise and omega-3 fatty acid (n3PUFA) supplementation is an effective treatment for hepatic steatosis in obese, hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods. Male OLETF rats were divided into 4 groups (n = 8/group): (1) remained sedentary (SED), (2) access to running wheels; (EX) (3) a diet supplemented with 3% of energy from fish oil (n3PUFA-SED); and (4) n3PUFA supplementation plus EX (n3PUFA+EX). The 8 week treatments began at 13 weeks, when hepatic steatosis is present in OLETF-SED rats. Results. EX alone lowered hepatic triglyceride (TAG) while, in contrast, n3PUFAs failed to lower hepatic TAG and blunted the ability of EX to decrease hepatic TAG levels in n3PUFAs+EX. Insulin sensitivity was improved in EX animals, to a lesser extent in n3PUFA+EX rats, and did not differ between n3PUFA-SED and SED rats. Only the EX group displayed higher complete hepatic fatty acid oxidation (FAO) to CO2 and carnitine palmitoyl transferase-1 activity. EX also lowered hepatic fatty acid synthase protein while both EX and n3PUFA+EX decreased stearoyl CoA desaturase-1 protein. Conclusions. Exercise lowers hepatic steatosis through increased complete hepatic FAO, insulin sensitivity, and reduced expression of de novo fatty acid synthesis proteins while n3PUFAs had no effect.
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Morris EM, Rector RS, Thyfault JP, Ibdah JA. Mitochondria and redox signaling in steatohepatitis. Antioxid Redox Signal 2011; 15:485-504. [PMID: 21128703 PMCID: PMC3118705 DOI: 10.1089/ars.2010.3795] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Alcoholic and nonalcoholic fatty liver diseases are potentially pathological conditions that can progress to steatohepatitis, fibrosis, and cirrhosis. These conditions affect millions of people throughout the world in part through poor lifestyle choices of excess alcohol consumption, overnutrition, and lack of regular physical activity. Abnormal mitochondrial and cellular redox homeostasis has been documented in steatohepatitis and results in alterations of multiple redox-sensitive signaling cascades. Ultimately, these changes in signaling lead to altered enzyme function and transcriptional activities of proteins critical to mitochondrial and cellular function. In this article, we review the current hypotheses linking mitochondrial redox state to the overall pathophysiology of alcoholic and nonalcoholic steatohepatitis and briefly discuss the current therapeutic options under investigation.
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Affiliation(s)
- E Matthew Morris
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Missouri, Columbia, Missouri 65212, USA
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37
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Buechler C, Wanninger J, Neumeier M. Adiponectin, a key adipokine in obesity related liver diseases. World J Gastroenterol 2011; 17:2801-11. [PMID: 21734787 PMCID: PMC3120939 DOI: 10.3748/wjg.v17.i23.2801] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Revised: 11/17/2010] [Accepted: 11/24/2010] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprising hepatic steatosis, non-alcoholic steatohepatitis (NASH), and progressive liver fibrosis is considered the most common liver disease in western countries. Fatty liver is more prevalent in overweight than normal-weight people and liver fat positively correlates with hepatic insulin resistance. Hepatic steatosis is regarded as a benign stage of NAFLD but may progress to NASH in a subgroup of patients. Besides liver biopsy no diagnostic tools to identify patients with NASH are available, and no effective treatment has been established. Visceral obesity is a main risk factor for NAFLD and inappropriate storage of triglycerides in adipocytes and higher concentrations of free fatty acids may add to increased hepatic lipid storage, insulin resistance, and progressive liver damage. Most of the adipose tissue-derived proteins are elevated in obesity and may contribute to systemic inflammation and liver damage. Adiponectin is highly abundant in human serum but its levels are reduced in obesity and are even lower in patients with hepatic steatosis or NASH. Adiponectin antagonizes excess lipid storage in the liver and protects from inflammation and fibrosis. This review aims to give a short survey on NAFLD and the hepatoprotective effects of adiponectin.
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Touzin NT, Bush KN, Williams CD, Harrison SA. Prevalence of colonic adenomas in patients with nonalcoholic fatty liver disease. Therap Adv Gastroenterol 2011; 4:169-76. [PMID: 21694801 PMCID: PMC3105612 DOI: 10.1177/1756283x11402118] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Epidemiologic data suggest that colonic adenomas have an increased tendency to occur in patients who are obese, African American, or have a positive family history of colon cancer, or diabetes mellitus. Recent data suggest that impaired glucose tolerance, dyslipidemia, and metabolic syndrome are associated with a higher risk for colonic adenomas. Patients with nonalcoholic fatty liver disease (NAFLD) often share several of the aforementioned risk factors for colonic adenomas. However, data are lacking about the relationship between NAFLD and colonic adenomas. The aim of this study was to systematically evaluate whether NAFLD is an independent risk factor for colonic adenomas. METHODS We performed a retrospective cohort observational study on 233 patients who underwent screening colonoscopies at Brooke Army Medical Center from November 2007 to March 2010 to assess for the association between NAFLD and colonic adenomas. Patients who had previously been found to have biopsy-proven simple steatosis (n = 65) or nonalcoholic steatohepatitis (NASH) (n = 29) were compared with a control group without fatty liver disease on sonographic imaging (n = 139). Patients were stratified based on gender, race, body mass index (BMI), and family history and adjusted for variables previously known to be associated with increased adenoma risk. RESULTS The mean age was 54.7 ± 6.0 years (48.5% women). Racial demographics were: 62.7% White, 18.5% Hispanic, 13.7%, African American, and 5.2% other. The mean BMI was 29.7 ± 5.8. The prevalence of colonic adenomas was 25.1% in the control group and 24.4% in the NAFLD group to include simple steatosis and NASH (p = 1.00). Furthermore, when adjusting for known confounders to include race, BMI, and family history no significant differences were found (p = 0.33). However, the ultrasound-negative patients ranked lower in the number of adenomas per person (p = 0.016). CONCLUSIONS There was no difference in the prevalence of colonic adenomas when comparing the NAFLD group who had undergone colonoscopy with a group of control patients without NAFLD who had undergone colonoscopy. However, patients with negative ultrasounds appeared to have a lower polyp burden.
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Affiliation(s)
- Nadege T. Touzin
- Gastroenterology and Hepatology Service, Wilford Hall Medical Center, San Antonio, Texas, USA
| | - Kelvin N.V. Bush
- Department of Medicine, Wilford Hall Medical Center, San Antonio, Texas, USA
| | - Christopher D. Williams
- Gastroeneterology and Hepatology Service, Wilford Hall Medical Center, San Antonio, Texas, USA
| | - Stephen A. Harrison
- Division of Gastroenterology and Hepatology, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, San Antonio, TX 78234, USA
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Prikoszovich T, Winzer C, Schmid AI, Szendroedi J, Chmelik M, Pacini G, Krssák M, Moser E, Funahashi T, Waldhäusl W, Kautzky-Willer A, Roden M. Body and liver fat mass rather than muscle mitochondrial function determine glucose metabolism in women with a history of gestational diabetes mellitus. Diabetes Care 2011; 34:430-6. [PMID: 20978097 PMCID: PMC3024362 DOI: 10.2337/dc10-1002] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Ectopic lipid storage in muscle (intramyocellular lipids [IMCL]) and liver (hepatocellular lipids [HCL]) coexists with impaired myocellular flux through ATP synthase (fATPase) in certain cohorts with increased risk of type 2 diabetes. Because women with a history of gestational diabetes mellitus (pGDM) have elevated ectopic lipids and diabetes risk, we tested whether deteriorated energy metabolism contributes to these abnormalities. RESEARCH DESIGN AND METHODS A total of 23 glucose-tolerant nonobese pGDM and eight women with normal glucose metabolism during pregnancy with similar age, body mass, and physical activity underwent oral glucose tolerance tests (OGTT) and intravenous glucose tolerance tests at 4-5 years after delivery. OGTT values <463 mL ⋅ min(-1) ⋅ m(-2) were considered to indicate insulin resistance. pGDM were further stratified into insulin-resistant (pGDM-IR) and insulin-sensitive (pGDM-IS) groups. IMCL, HCL, and fATPase were measured with (1)H/(31)P magnetic resonance spectroscopy. RESULTS pGDM had 36% higher fat mass and 12% lower insulin sensitivity. Log-transformed fATPase was lower in pGDM (10.6 ± 3.8 µmol ⋅ mL muscle(-1) ⋅ min(-1) vs. 12.1 ± 1.4 µmol ⋅ mL muscle(-1) ⋅ min(-1), P < 0.03) and related to plasma adiponectin after adjustment for body fat (r = 0.44, P < 0.04). IMCL were 61% and 69% higher in pGDM-IR (P < 0.05 vs. pGDM-IS) and insulin resistant women (P < 0.003 vs. insulin sensitive), respectively. HCL were doubled (P < 0.05) in pGDM and insulin resistant women, and correlated positively with body fat mass (r = 0.50, P < 0.01) and inversely with insulin sensitivity (r = -0.46, P < 0.05). CONCLUSIONS Glucose-tolerant pGDM show increased liver fat but only slightly lower muscular insulin sensitivity and ATP synthesis. This suggests that alteration of hepatic lipid storage represents an early and predominant abnormality in this cohort.
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Affiliation(s)
- Thomas Prikoszovich
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Meisamy S, Hines CDG, Hamilton G, Sirlin CB, McKenzie CA, Yu H, Brittain JH, Reeder SB. Quantification of hepatic steatosis with T1-independent, T2-corrected MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy. Radiology 2011; 258:767-75. [PMID: 21248233 DOI: 10.1148/radiol.10100708] [Citation(s) in RCA: 316] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE To prospectively compare an investigational version of a complex-based chemical shift-based fat fraction magnetic resonance (MR) imaging method with MR spectroscopy for the quantification of hepatic steatosis. MATERIALS AND METHODS This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained before all studies. Fifty-five patients (31 women, 24 men; age range, 24-71 years) were prospectively imaged at 1.5 T with quantitative MR imaging and single-voxel MR spectroscopy, each within a single breath hold. The effects of T2 correction, spectral modeling of fat, and magnitude fitting for eddy current correction on fat quantification with MR imaging were investigated by reconstructing fat fraction images from the same source data with different combinations of error correction. Single-voxel T2-corrected MR spectroscopy was used to measure fat fraction and served as the reference standard. All MR spectroscopy data were postprocessed at a separate institution by an MR physicist who was blinded to MR imaging results. Fat fractions measured with MR imaging and MR spectroscopy were compared statistically to determine the correlation (r(2)), and the slope and intercept as measures of agreement between MR imaging and MR spectroscopy fat fraction measurements, to determine whether MR imaging can help quantify fat, and examine the importance of T2 correction, spectral modeling of fat, and eddy current correction. Two-sided t tests (significance level, P = .05) were used to determine whether estimated slopes and intercepts were significantly different from 1.0 and 0.0, respectively. Sensitivity and specificity for the classification of clinically significant steatosis were evaluated. RESULTS Overall, there was excellent correlation between MR imaging and MR spectroscopy for all reconstruction combinations. However, agreement was only achieved when T2 correction, spectral modeling of fat, and magnitude fitting for eddy current correction were used (r(2) = 0.99; slope ± standard deviation = 1.00 ± 0.01, P = .77; intercept ± standard deviation = 0.2% ± 0.1, P = .19). CONCLUSION T1-independent chemical shift-based water-fat separation MR imaging methods can accurately quantify fat over the entire liver, by using MR spectroscopy as the reference standard, when T2 correction, spectral modeling of fat, and eddy current correction methods are used.
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Affiliation(s)
- Sina Meisamy
- Liver Imaging Research Program, Department of Radiology, University of Wisconsin, 600 Highland Ave, E3/311 CSC, Madison, WI 53792-3252, USA.
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Yokoo T, Shiehmorteza M, Hamilton G, Wolfson T, Schroeder ME, Middleton MS, Bydder M, Gamst AC, Kono Y, Kuo A, Patton HM, Horgan S, Lavine JE, Schwimmer JB, Sirlin CB. Estimation of hepatic proton-density fat fraction by using MR imaging at 3.0 T. Radiology 2011; 258:749-59. [PMID: 21212366 DOI: 10.1148/radiol.10100659] [Citation(s) in RCA: 237] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE To compare the accuracy of several magnetic resonance (MR) imaging-based methods for hepatic proton-density fat fraction (FF) estimation at 3.0 T, with spectroscopy as the reference technique. MATERIALS AND METHODS This prospective study was institutional review board approved and HIPAA compliant. Informed consent was obtained. One hundred sixty-three subjects (39 with known hepatic steatosis, 110 with steatosis risk factors, 14 without risk factors) underwent proton MR spectroscopy and non-T1-weighted gradient-echo MR imaging of the liver. At spectroscopy, the reference FF was determined from frequency-selective measurements of fat and water proton densities. At imaging, FF was calculated by using two-, three-, or six-echo methods, with single-frequency and multifrequency fat signal modeling. The three- and six-echo methods corrected for T2*; the two-echo methods did not. For each imaging method, the fat estimation accuracy was assessed by using linear regression between the imaging FF and spectroscopic FF. Binary classification accuracy of imaging was assessed at four reference spectroscopic thresholds (0.04, 0.06, 0.08, and 0.10 FF). RESULTS Regression intercept of two-, three-, and six-echo methods were -0.0211, 0.0087, and -0.0062 (P <.001 for all three) without multifrequency modeling and -0.0237 (P <.001), 0.0022, and -0.0007 with multifrequency modeling, respectively. Regression slope of two-, three-, and six-echo methods were 0.8522, 0.8528, and 0.7544 (P <.001 for all three) without multifrequency modeling and 0.9994, 0.9775, and 0.9821 with multifrequency modeling, respectively. Significant deviation of intercept and slope from 0 and 1, respectively, indicated systematic error. Classification accuracy was 82.2%-90.1%, 93.9%-96.3%, and 83.4%-89.6% for two-, three-, and six-echo methods without multifrequency modeling and 88.3%-92.0%, 95.1%-96.3%, and 94.5%-96.3% with multifrequency modeling, respectively, depending on the FF threshold. T2*-corrected (three- and six-echo) multifrequency imaging methods had the overall highest FF estimation and classification accuracy. Among methods without multifrequency modeling, the T2-corrected three-echo method had the highest accuracy. CONCLUSION Non-T1-weighted MR imaging with T2 correction and multifrequency modeling helps accurately estimate hepatic proton-density FF at 3.0 T.
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Affiliation(s)
- Takeshi Yokoo
- Department of Radiology, University of California at San Diego, 408 Dickinson St, San Diego, CA 92103-8592, USA
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Treeprasertsuk S, Lopez-Jimenez F, Lindor KD. Nonalcoholic fatty liver disease and the coronary artery disease. Dig Dis Sci 2011; 56:35-45. [PMID: 20464495 DOI: 10.1007/s10620-010-1241-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Accepted: 04/06/2010] [Indexed: 12/23/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and is recognized as part of the metabolic syndrome (MetS). Patients with NAFLD have a lower life expectancy compared to the general population, with coronary artery disease (CAD) as the leading cause of death. AIMS We aim to address the epidemiological data of CAD, the possible pathogenesis or linkage mechanisms of NAFLD and atherosclerosis and the strategies to reduce the CAD risk in NAFLD patients. METHODS We reviewed data from a Medline and PubMed search which was performed to identify relevant literature using search terms "NAFLD," "metabolic syndrome" and "coronary artery disease." RESULTS Patients with steatohepatitis, a part of the spectrum of NAFLD, have more cardiovascular events than patients without steatohepatitis. However, the association between liver histological progression and the risk of CAD events is not linear. A multidisciplinary approach to NAFLD patients based on controlling related risk factors and monitoring for CAD risks and liver complications is necessary. The combination of lifestyle modification with pharmacological treatment tailored to each individual's risk factors needs to be considered. There is a need for more research on primary prevention for CAD in NAFLD patients and interventional studies for determining the nature of the relationship between NAFLD and CAD. CONCLUSIONS NAFLD is recognized as part of the MetS and increases cardiovascular risks. Therefore, a multidisciplinary approach to these patients of controlling the related risk factors and monitoring for cardiovascular and liver complications must be done.
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Affiliation(s)
- Sombat Treeprasertsuk
- Division of Gastroenterology and Hepatology, Mayo Clinic, Fiterman Center for Digestive Diseases, 200 First Street, SW, Rochester, MN 55905, USA.
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Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140:124-31. [PMID: 20858492 DOI: 10.1053/j.gastro.2010.09.038] [Citation(s) in RCA: 1613] [Impact Index Per Article: 115.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Revised: 08/03/2010] [Accepted: 09/09/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Prevalence of nonalcoholic fatty liver disease (NAFLD) has not been well established. The purpose of this study was to prospectively define the prevalence of both NAFLD and nonalcoholic steatohepatitis (NASH). METHODS Outpatients 18 to 70 years old were recruited from Brooke Army Medical Center. All patients completed a baseline questionnaire and ultrasound. If fatty liver was identified, then laboratory data and a liver biopsy were obtained. RESULTS Four hundred patients were enrolled. Three hundred and twenty-eight patients completed the questionnaire and ultrasound. Mean age (range, 28-70 years) was 54.6 years (7.35); 62.5% Caucasian, 22% Hispanic, and 11.3% African American; 50.9% female; mean body mass index (BMI) (calculated as kg/m(2)) was 29.8 (5.64); and diabetes and hypertension prevalence 16.5% and 49.7%, respectively. Prevalence of NAFLD was 46%. NASH was confirmed in 40 patients (12.2% of total cohort, 29.9% of ultrasound positive patients). Hispanics had the highest prevalence of NAFLD (58.3%), then Caucasians (44.4%) and African Americans (35.1%). NAFLD patients were more likely to be male (58.9%), older (P = .004), hypertensive (P < .00005), and diabetic (P < .00005). They had a higher BMI (P < .0005), ate fast food more often (P = .049), and exercised less (P = 0.02) than their non-NAFLD counterparts. Hispanics had a higher prevalence of NASH compared with Caucasians (19.4% vs 9.8%; P = .03). Alanine aminotransferase, aspartate aminotransferase, BMI, insulin, Quantitative Insulin-Sensitivity Check Index, and cytokeratin-18 correlated with NASH. Among the 54 diabetic patients, NAFLD was found in 74% and NASH in 22.2%. CONCLUSION Prevalence of NAFLD and NASH is higher than estimated previously. Hispanics and patients with diabetes are at greatest risk for both NAFLD and NASH.
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Affiliation(s)
- Christopher D Williams
- Gastroenterology and Hepatology Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, Texas 78234, USA
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Abstract
Intracellular fat accumulation is common feature of liver disease. Intracellular fat (steatosis) is the histologic hallmark of nonalcoholic fatty liver disease but also may occur with alcohol abuse, viral hepatitis, HIV and genetic lipodystrophies, and chemotherapy. This article reviews emerging MR imaging techniques that attempt to quantify liver fat. The content provides an overview of fatty liver disease and diseases where fat is an important disease feature. Also discussed is the current use and limitation of nontargeted biopsy in diffuse liver disease and why quantitative noninvasive biomarkers of liver fat would be beneficial.
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Affiliation(s)
- Scott B Reeder
- Liver Imaging Research Program, Department of Radiology, University of Wisconsin, E1/374 CSC, 600 Highland Avenue, Madison, WI 53792-3252, USA.
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Liu Q, Bengmark S, Qu S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis 2010; 9:42. [PMID: 20426802 PMCID: PMC2873482 DOI: 10.1186/1476-511x-9-42] [Citation(s) in RCA: 156] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2010] [Accepted: 04/28/2010] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease is increasingly regarded as a hepatic manifestation of metabolic syndrome, and the severity of nonalcoholic fatty liver disease seems to increase in parallel with other features of metabolic syndrome. Excess lipid accumulation in the liver cells is not only a mediator of Metabolic Syndrome and indicator of a lipid overload but also accompanied by a range of histological alterations varying from 'simple' steatosis to nonalcoholic steatohepatitis, with time progressing to manifest cirrhosis. Hepatocellular carcinoma may also occur in nonalcoholic steatohepatitis -related cirrhosis with a mortality rate similar to or worse than for cirrhosis associated with hepatitis C. This review summarizes the knowledge about the causal relationship between hepatic fat accumulation, insulin resistance, liver damage and the etiological role of hepatic fat accumulation in pathogenesis of extra- and intra-hepatic manifestations. Special emphasis is given suggestions of new targets treatment and prevention of nonalcoholic fatty liver disease.
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Affiliation(s)
- Qing Liu
- Deaprtment of Endocrinology, Tenth People's Hospital, Tongji University, Shanghai 200072, China
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46
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Kistler KD, Molleston J, Unalp A, Abrams SH, Behling C, Schwimmer JB. Symptoms and quality of life in obese children and adolescents with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2010; 31:396-406. [PMID: 19863497 PMCID: PMC2807909 DOI: 10.1111/j.1365-2036.2009.04181.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Data on the quality of life (QOL) of children with non-alcoholic fatty liver disease (NAFLD) are needed to estimate the true burden of illness in children with NAFLD. AIM To characterize QOL and symptoms of children with NAFLD and to compare QOL in children with NAFLD with that in a sample of healthy children. METHODS Quality of life and symptoms were assessed in children with biopsy-proven NAFLD enrolled in the NASH Clinical Research Network. PedsQL scores were compared with scores from healthy children. For children with NAFLD, between-group comparisons were made to test associations of demography, histological severity, symptoms and QOL. RESULTS A total of 239 children (mean age 12.6 years) were studied. Children with NAFLD had worse total (72.8 vs. 83.8, P < 0.01), physical (77.2 vs. 87.5, P < 0.01) and psychosocial health (70.4 vs. 81.9, P < 0.01) scores compared with healthy children. QOL scores did not significantly differ by histological severity of NAFLD. Fatigue, trouble sleeping and sadness accounted for almost half of the variance in QOL scores. Impaired QOL was present in 39% of children with NAFLD. CONCLUSIONS Children with NAFLD have a decrement in QOL. Symptoms were a major determinant of this impairment. Interventions are needed to restore and optimize QOL in children with NAFLD.
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Affiliation(s)
- K. D. Kistler
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego, La Jolla, CA,Joint Doctoral Program in Public Health, San Diego State University and University of California San Diego, La Jolla, CA
| | - J. Molleston
- Pediatric Gastroenterology, Hepatology and Nutrition, James Whitcomb Riley Hospital for Children, Indianapolis, IN
| | - A. Unalp
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - S. H. Abrams
- Texas Children's Hospital, Houston, TX,Baylor College of Medicine, Houston, TX
| | - C. Behling
- Pacific Rim Pathology Group, Sharp Memorial Hospital, San Diego, CA
| | - J. B. Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego, La Jolla, CA,Department of Gastroenterology, Rady Children's Hospital, San Diego, CA
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Lindbäck SM, Gabbert C, Johnson BL, Smorodinsky E, Sirlin CB, Garcia N, Pardee PE, Kistler KD, Schwimmer JB. Pediatric nonalcoholic fatty liver disease: a comprehensive review. Adv Pediatr 2010; 57:85-140. [PMID: 21056736 DOI: 10.1016/j.yapd.2010.08.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Sarah M Lindbäck
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, 200 West Arbor Drive, San Diego, CA 92103-8450, USA
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Abstract
Current imaging methodologies can detect steatosis with increasing accuracy but cannot detect inflammation or pre-cirrhotic fibrosis or remodeling of the liver parenchyma. Imaging also cannot assess types or localization of hepatic steatosis. With the increased use of rodents to study NAFLD/NASH, careful analysis or reading highlights the fact that liver tissue evaluations reported in many of the popular animal models of NAFLD/NASH often do not imitate many of the significant aspects of the human disease, despite similar terminology applied by investigators. This review will focus on the findings in human disease.
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Affiliation(s)
- Elizabeth M Brunt
- Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave, Box 8118, St. Louis, MO 63110, USA.
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