Application of Ultrasound and Shear Wave Elastography Imaging in a Rat Model of NAFLD/NASH

Morin, Jeffrey; Swanson, Terri A.; Rinaldi, Anthony; Boucher, Magalie; Ross, Trenton T.; Hirenallur-Shanthappa, Dinesh

doi:10.3791/62403

Cited by 14 publications

(12 citation statements)

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“…The highest histologic correlates for stiffness and echogenicity were fibrosis and macrosteatosis, respectively, with imaging metrics closely tracking the temporal dynamics of the histological scores. Liver stiffness measurements, additionally, were in good agreement with other SWE studies in CDAHFD rodents (23) as well as human SWE imaging in patients with NASH. (4) Importantly, these noninvasive measurements could be taken in a highly repeatable and simple manner, eliminating many of the user-dependent challenges faced by traditional handheld ultrasound scanning (e.g., consistent beam placement, precompression of tissue biasing stiffness).…”

Section: B Asupporting

confidence: 83%

“…( 2 ) Over the past decade, clinical research has demonstrated that SWE and other ultrasound readouts (such as echogenicity, backscatter coefficient, and/or attenuation) are safe and effective at diagnosing a multitude of liver pathologies in humans, including steatosis, ( 3 ) fibrosis/cirrhosis, ( 4 ) and cancer, ( 5 ) and have greatly reduced the reliance on invasive biopsy. ( 6 ) While the integration of SWE, and corollary technologies such as transient elastography, in clinical practice has progressed at a robust pace, there has been a notable lack of adoption of these technologies in preclinical research, despite a growing list of publications demonstrating the feasibility of the approach in rodent models (mice ( 7 , 8 , 9 ) and rats ( 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ) ) and relevancy of these models to human liver stiffness measurements. ( 24 ) Basic science laboratories still mostly rely on histology to assess hepatic injury and response to therapy, ( 25 , 26 , 27 , 28 ) which hampers longitudinal studies because it requires subject endpoints, thus increasing the individuals enrolled and costs.…”

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confidence: 99%

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Development of a Robotic Shear Wave Elastography System for Noninvasive Staging of Liver Disease in Murine Models

et al. 2022

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Shear wave elastography (SWE) is an ultrasound-based stiffness quantification technology that is used for noninvasive liver fibrosis assessment. However, despite widescale clinical adoption, SWE is largely unused by preclinical researchers and drug developers for studies of liver disease progression in small animal models due to significant experimental, technical, and reproducibility challenges. Therefore, the aim of this work was to develop a tool designed specifically for assessing liver stiffness and echogenicity in small animals to better enable longitudinal preclinical studies. A highfrequency linear array transducer (12-24 MHz) was integrated into a robotic small animal ultrasound system (Vega; SonoVol, Inc., Durham, NC) to perform liver stiffness and echogenicity measurements in three dimensions. The instrument was validated with tissue-mimicking phantoms and a mouse model of nonalcoholic steatohepatitis. Female C57BL/6J mice (n = 40) were placed on choline-deficient, L-amino acid-defined, high-fat diet and imaged longitudinally for 15 weeks. A subset was sacrificed after each imaging timepoint (n = 5) for histological validation, and analyses of receiver operating characteristic (ROC) curves were performed. Results demonstrated that robotic measurements of echogenicity and stiffness were most strongly correlated with macrovesicular steatosis (R 2 = 0.891) and fibrosis (R 2 = 0.839), respectively. For diagnostic classification of fibrosis (Ishak score), areas under ROC (AUROCs) curves were 0.969 for ≥Ishak1, 0.984 for ≥Ishak2, 0.980 for ≥Ishak3, and 0.969 for ≥Ishak4. For classification of macrovesicular steatosis (S-score), AUROCs were 1.00 for ≥S2 and 0.997 for ≥S3. Average scanning and analysis time was <5 minutes/liver. Conclusion: Robotic SWE in small animals is feasible and sensitive to small changes in liver disease state, facilitating in vivo staging of rodent liver disease with minimal sonographic expertise. (Hepatology Communications 2022;6:1827-1839).U ltrasound-based shear wave elastography (SWE) is a revolutionary imaging technique that noninvasively measures the mechanical stiffness of biological tissue, such as liver, in vivo. (1) In SWE, a high-intensity ultrasonic pulse is used to generate transverse mechanical waves in the tissue (i.e.,

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Section: B Asupporting

confidence: 83%

mentioning

confidence: 99%

Development of a Robotic Shear Wave Elastography System for Noninvasive Staging of Liver Disease in Murine Models

et al. 2022

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“…Previous animal studies 29 indicated that SWS can be used to assess disease phenotype and progression in preclinical models of NAFLD/NASH. SWS has been proven to have high diagnostic value in the stage of liver brosis, and has been recommended in the non-invasive assessment of liver brosis by major guidelines and expert opinions 19,30,31 .This study further explored the value of SWS in the differential diagnosis of NASH.…”

Section: Discussionmentioning

confidence: 99%

Technical acoustic measurements combined with clinical parameters for differential diagnosis of nonalcoholic steatohepatitis

Zhao

Qiu

Dong

et al. 2023

Preprint

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Background and aim Diagnosing NASH is challenging. This study intended to explore the diagnostic value of multiple technical acoustic measurements in the diagnosis of NASH, and to establish a diagnostic model combining technical acoustic measurements with clinical parameters to improve the diagnostic efficacy of NASH. Methods We consecutively enrolled 75 patients with clinically suspected NAFLD who underwent percutaneous liver biopsy in our hospital from June 2020 to December 2021. All cases underwent multiple advanced acoustic measurements for liver such as SWD, SWS, ATI, NLV, and Ratio examination before liver biopsies. A nomogram prediction model combining the technical acoustic measurements and clinical parameters was established and the model is proposed to improve the diagnostic performance of NASH. Results A total of 75 cases were included in this study. Classification of Pathological grade for NASH was as follows: normal liver, (n=15, 20%), NAFL, (n=44, 58.7%), and NASH, (n=16, 21.3%). There were statistically significant differences in SWS (p=0.002), AC (p=0.018), NLV (p=0.033), age (p=0.013) and Glucose (Glu) (p=0.049) between NASH and non-NASH. A nomogram model which includes SWS, AC, NLV, age and Glu was built to predict NASH, and the calibration curves showed good calibrations in both training and validation sets. The AUCs of the combined nomogram model for the training set and validation set were 0.8597 and 0.7794, respectively. Conclusion There were statistically significant differences in SWS, AC, NLV, age and Glu between NASH and non-NASH. A nomogram model which includes SWS, AC, NLV, age and Glu was built to predict NASH. The predictive model has a higher diagnostic performance than a single factor model in the diagnosis of NASH, and has a good clinical application prospect.

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“…Dual MCT1KO in hepatocytes plus hepatic stellate cells showed no change in overall fibrosis, similar to the Chol-MCT1-siRNA results (Figure 5G, 5H). Additionally, liver stiffness was monitored via ultrasound-based shear wave elastography (SWE) in a noninvasive diagnostic mode for liver disease 48,49 .…”

Section: Hepatocyte-specific Mct1ko Accelerated Fibrosis While Hepati...mentioning

confidence: 99%

“…Mouse liver stiffness was monitored by Vega robotic ultrasound imager, SonoEQ 1.14.0 (SonoVol), as described in a previous study 48 . Before SWE measurement, mice had their abdomen hair shaved and the residual hair was removed using chemical depilation cream (Nair).…”

Section: Shear Wave Elastography (Swe)mentioning

confidence: 99%

Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis

Min

Yenilmez

Kelly

et al. 2023

Preprint

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Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1fl/fl mice on a choline deficient, high fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri-N-acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 appears not to be an attractive therapeutic target for NASH.

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Application of Ultrasound and Shear Wave Elastography Imaging in a Rat Model of NAFLD/NASH

Cited by 14 publications

References 0 publications

Development of a Robotic Shear Wave Elastography System for Noninvasive Staging of Liver Disease in Murine Models

Development of a Robotic Shear Wave Elastography System for Noninvasive Staging of Liver Disease in Murine Models

Technical acoustic measurements combined with clinical parameters for differential diagnosis of nonalcoholic steatohepatitis

Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis

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