Clinical trial NCT05802199: Quantitative Detection Efficiency of UDFF for Nonalcoholic Fatty Liver Disease
Official title: Quantitative Detection Efficiency of Ultrasound Derived Fat Fraction (UDFF) as a Non-invasive Alternative for Nonalcoholic Fatty Liver Disease (CHESS2303): a Multicenter Prospective Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Non-alcoholic Fatty Liver Disease
Keywords: non-alcoholic fatty liver disease (NAFLD)
ultrasound-derived fat fraction (UDFF)
hepatic fibrosis
point shear wave elastography
Lead sponsor: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Sponsor class: OTHER
Collaborators: name: Zhongda Hospital
name: Zhejiang University
name: Lishui Country People's Hospital
name: Shandong Public Health Clinical Center
name: Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine
name: First Affiliated Hospital of Wenzhou Medical University
name: The First Affiliated Hospital with Nanjing Medical University
name: The Second Hospital of Anhui Medical University
name: The People's Hospital of Bozhou
name: The First Affiliated Hospital of Xiamen University
name: The First Hospital of Jilin University
name: Kliniken Hirslanden Beau Site, Salem und Permancence
name: Third People's Hospital of Zhenjiang, Jiangsu University
First posted: 2023-04-06
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients were fulfilled diagnosis of non-alcoholic fatty liver disease based on radiological and clinical manifestation.

Brief summary: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, affecting more than 25 % of the population globally. Approximately 20 % - 25 % of NAFLD patients can develop nonalcoholic steatohepatitis (NASH), which leads to more rapid progression from fibrosis to cirrhosis, and even liver failure or hepatocellular carcinoma (HCC). Early detection and treatment may halt or reverse NAFLD progression.

Although liver biopsy has been the well-accepted clinical reference standard for both diagnosis and staging of the different histological changes in NAFLD, this procedure is invasive with complications such as bleeding and infection, and is unreliable for quantifying steatosis due to sampling errors. Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) currently has been accepted as the preferred alternative to the histological assessment of hepatic steatosis in patients with NAFLD. Magnetic resonance elastography (MRE) provide additional information of inflammation and fibrotic components of NAFLD. However, important limitations hinder the widespread clinical application of MRI, including high cost, low availability, long scan times and exclusion of patients with metal implants.

Ultrasound (US) has been recommended by several guidelines as the first-line screening tool for patients at risk of NAFLD. The developed ultrasound-derived fat fraction (UDFF) is designed to assess hepatic steatosis by estimating the frequency-dependent attenuation coefficient (AC) and backscatter coefficient (BSC) through processing acoustic radiofrequency (RF) signals returned from the liver tissue as fat vesicles in hepatocytes have a different characteristic impedance compared to normal liver tissue. UDFF is available on the Acuson Sequoia ultrasound system (Simens Healthineers, Mountain View, CA, USA), with reference to integrated phantom data to correct for system impact, and produces a UDFF value presented as a fat fraction (%), which is potentially related to MRI-PDFF and can be directly compared with MRI-PDFF. In addition, automatic point shear wave elastography (auto-pSWE) is available on the Acuson Sequoia ultrasound system to obtain liver stiffness measurement (LSM) for assessing hepatic fibrosis, simultaneously with UDFF measurement. The prospective, multicenter study aims to evaluate the efficiency of UDFF as a quantitative non-invasive alternative for NAFLD.

Detailed description: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide characterized by excessive accumulation of triglycerides in hepatocytes and subsequent steatosis, affecting more than 25 % of the population globally. Approximately 20 % - 25 % of NAFLD patients can develop nonalcoholic steatohepatitis (NASH), which leads to more rapid progression from fibrosis to cirrhosis, and even liver failure or hepatocellular carcinoma (HCC). NALFD is strongly associated with metabolic risk factors, such as obesity, cardiovascular disease, and diabetes mellitus. Early detection and treatment may halt or reverse NAFLD progression. However, the occurrence and progression of steatosis and fibrosis had no obvious clinical symptoms, resulting in a difficulty of early diagnose and grade individuals with NAFLD clinically.

Although liver biopsy has been the well-accepted clinical reference standard for both diagnosis and staging of the different histological changes in NAFLD, this procedure is invasive with complications such as bleeding and infection, and is unreliable for quantifying steatosis due to sampling errors. Several imaging modalities have been used to diagnose and grade hepatic steatosis. Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) currently has been accepted as the preferred alternative to the histological assessment of hepatic steatosis in patients with NAFLD. Magnetic resonance elastography (MRE) provide additional information of inflammation and fibrotic components of NAFLD. However, important limitations hinder the widespread clinical application of MRI, including high cost, low availability, long scan times and exclusion of patients with metal implants.

Ultrasound (US) has been recommended by several guidelines as the first-line screening tool for patients at risk of NAFLD. The most commonly used noninvasive method that quantifies the amount of fat in the liver is the controlled attenuation parameter, and more than 10% of steatosis can be distinguished. The disadvantages of this technique are that the liver morphological changes cannot be assessed simultaneously and poor performance in patients with higher body mass indices, leading to a failure rate of measurement ranged of 7.7 % - 14.0 %.

The developed ultrasound-derived fat fraction (UDFF) is designed to assess hepatic steatosis by estimating the frequency-dependent attenuation coefficient (AC) and backscatter coefficient (BSC) through processing acoustic radiofrequency (RF) signals returned from the liver tissue as fat vesicles in hepatocytes have a different characteristic impedance compared to normal liver tissue. UDFF is available on the Acuson Sequoia ultrasound system (Simens Healthineers, Mountain View, CA, USA), with reference to integrated phantom data to correct for system impact, and produces a UDFF value presented as a fat fraction (%), which is potentially related to MRI-PDFF and can be directly compared with MRI-PDFF. In addition, automatic point shear wave elastography (auto-pSWE) is available on the Acuson Sequoia ultrasound system to obtain liver stiffness measurement (LSM) for assessing hepatic fibrosis, simultaneously with UDFF measurement. The prospective, multicenter study aims to evaluate the efficiency of UDFF as a quantitative non-invasive alternative for NAFLD.

Eligibility criteria: Inclusion Criteria:

1. be at least 18 years of age.
2. fulfilled diagnosis of non-alcoholic fatty liver disease based on radiological (MRI-PDFF values \> 5%) and clinical manifestation.
3. fulfilled diagnosis of hepatic fibrosis with non-alcoholic fatty liver disease based on radiological (LSM by MRE \> 3.02kPa) and clinical manifestation.
4. Willing to participate in this research and sign the informed consent.

Exclusion Criteria:

1. with liver dysfunction at the terminal stage or are ready for liver transplantation.
2. with viral hepatitis, autoimmune hepatitis, and alpha-1-antitrypsin deficiency.
3. history of excessive drinking (the amount of alcohol consumed by women is more than 140 grams per week, and that of men is more than 210 grams per week).
4. unable to cooperate with ultrasound examinations.
5. have taken liver damage drugs within the past six months.
6. with massive ascites.

Primary outcomes:
measure: The efficiency of UDFF (in %) for hepatic steatosis in comparison with MRI-PDFF (in %).
timeFrame: 1 years
Secondary outcomes:
measure: The efficiency of auto-pSWE (in kPa) for hepatic fibrosis in comparison with MRE (in kPa).
timeFrame: 1 years
Other outcomes:
Locations:
city: Bozhou
country: China
facility: The People's Hospital of Bozhou
state: Anhui
city: Hefei
country: China
facility: The Second Hospital of Anhui Medical University
state: Anhui
city: Xiamen
country: China
facility: The First Affiliated Hospital of Xiamen University
state: Fujian
city: Nanjing
country: China
facility: Zhongda Hospital, Southeast University
state: Jiangsu
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Zhenjiang
country: China
facility: Zhe Third People's Hospital of Zhenjiang
state: Jiangsu
city: Changchun
country: China
facility: The First Bethune Hospital of Jilin University
state: Jilin
city: Jinan
country: China
facility: Shandong Public Health Clinical Center
state: Shandong
city: Shanghai
country: China
facility: Xinhua Hospital, Shanghai Jiaotong University School of Medicine
state: Shanghai
city: Hangzhou
country: China
facility: Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine
state: Zhejiang
city: Lishui
country: China
facility: Lishui People's Hospital
state: Zhejiang
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
state: Zhejiang
city: Bern
country: Switzerland
facility: Kliniken Hirslanden Beau Site, Salem und Permancence
state: Kanton Bern
Study officials:
affiliation: Xinhua Hospital, Shanghai Jiaotong University School of Medicine
name: Jiangao Fan, M.D.
role: STUDY_CHAIR
affiliation: Zhongda Hospital
name: Xiaolong Qi, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Xinhua Hospital, Shanghai Jiaotong University School of Medicine
name: Yi Dong, M.D.
role: STUDY_DIRECTOR
References:
citation: Ferraioli G, Berzigotti A, Barr RG, Choi BI, Cui XW, Dong Y, Gilja OH, Lee JY, Lee DH, Moriyasu F, Piscaglia F, Sugimoto K, Wong GL, Wong VW, Dietrich CF. Quantification of Liver Fat Content with Ultrasound: A WFUMB Position Paper. Ultrasound Med Biol. 2021 Oct;47(10):2803-2820. doi: 10.1016/j.ultrasmedbio.2021.06.002. Epub 2021 Jul 18.
citation: Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, Ratziu V, McCullough A. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011 Jul;54(1):344-53. doi: 10.1002/hep.24376.
citation: Simon TG, Roelstraete B, Khalili H, Hagstrom H, Ludvigsson JF. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort. Gut. 2021 Jul;70(7):1375-1382. doi: 10.1136/gutjnl-2020-322786. Epub 2020 Oct 9.
citation: Zhang MH, Li J, Zhu XY, Zhang YQ, Ye ST, Leng YR, Yang T, Zhang H, Kong LY. Physalin B ameliorates nonalcoholic steatohepatitis by stimulating autophagy and NRF2 activation mediated improvement in oxidative stress. Free Radic Biol Med. 2021 Feb 20;164:1-12. doi: 10.1016/j.freeradbiomed.2020.12.020. Epub 2021 Jan 1.
citation: Chitturi S, Farrell GC, Hashimoto E, Saibara T, Lau GK, Sollano JD; Asia-Pacific Working Party on NAFLD. Non-alcoholic fatty liver disease in the Asia-Pacific region: definitions and overview of proposed guidelines. J Gastroenterol Hepatol. 2007 Jun;22(6):778-87. doi: 10.1111/j.1440-1746.2007.05001.x.
citation: European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 2016 Jun;59(6):1121-40. doi: 10.1007/s00125-016-3902-y. No abstract available.
citation: Kim SH, Lee JM, Kim JH, Kim KG, Han JK, Lee KH, Park SH, Yi NJ, Suh KS, An SK, Kim YJ, Son KR, Lee HS, Choi BI. Appropriateness of a donor liver with respect to macrosteatosis: application of artificial neural networks to US images--initial experience. Radiology. 2005 Mar;234(3):793-803. doi: 10.1148/radiol.2343040142. Epub 2005 Jan 21.
citation: Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, Clark JM. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011 Sep 2;54(3):1082-1090. doi: 10.1002/hep.24452.
citation: Dasarathy S, Dasarathy J, Khiyami A, Joseph R, Lopez R, McCullough AJ. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J Hepatol. 2009 Dec;51(6):1061-7. doi: 10.1016/j.jhep.2009.09.001. Epub 2009 Sep 20.
citation: Marshall RH, Eissa M, Bluth EI, Gulotta PM, Davis NK. Hepatorenal index as an accurate, simple, and effective tool in screening for steatosis. AJR Am J Roentgenol. 2012 Nov;199(5):997-1002. doi: 10.2214/AJR.11.6677.
citation: Webb M, Yeshua H, Zelber-Sagi S, Santo E, Brazowski E, Halpern Z, Oren R. Diagnostic value of a computerized hepatorenal index for sonographic quantification of liver steatosis. AJR Am J Roentgenol. 2009 Apr;192(4):909-14. doi: 10.2214/AJR.07.4016.
citation: Labyed Y, Milkowski A. Novel Method for Ultrasound-Derived Fat Fraction Using an Integrated Phantom. J Ultrasound Med. 2020 Dec;39(12):2427-2438. doi: 10.1002/jum.15364. Epub 2020 Jun 11.
citation: Gao J, Wong C, Maar M, Park D. Reliability of performing ultrasound derived SWE and fat fraction in adult livers. Clin Imaging. 2021 Dec;80:424-429. doi: 10.1016/j.clinimag.2021.08.025. Epub 2021 Sep 17.