Accuracy of Imaging Techniques in Diagnosing Steatohepatitis and Fibrosis in NAFLD Patients

Non-Alcoholic Fatty Liver Disease Clinical Trial

— ImagingNAFLD  

Official title:

Accuracy of Imaging Techniques Including Ultrasound and Magnetic Resonance Imaging in the Diagnosis of Steatohepatitis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease: Comparison With the Histological Reference Standard

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04785937
• Other study ID #: 859/2018/SPER/AUSLRE
• Status: Recruiting
• Phase: N/A
• Start date: January 1, 2019
• Est. completion date: June 1, 2022

Study information

• Verified date: March 2021
• Source: Azienda Unità Sanitaria Locale Reggio Emilia
• Contact: Giulia Besutti, MD
• Phone: +390522296369
• Email: giulia.besutti[@]ausl.re.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition, and when fatty liver is associated with inflammation and hepatocellular injury (steatohepatitis), it can lead to fibrosis, cirrhosis, liver failure and hepatocellular carcinoma. Liver biopsy is the gold standard for NAFLD assessment but has several drawbacks. Several drugs for NASH are now in phase 2-3 trials, and if medical treatments become available, non-invasive tools to identify patients who may benefit from a therapeutic intervention will be strongly needed. Some imaging methods have shown promising potential in fibrosis and NASH diagnosis. This study aims to evaluate the diagnostic accuracy of non-invasive imaging methods, including ultrasound (US) and Magnetic Resonance (MR) techniques, in diagnosing NASH and fibrosis in patients with or at high risk of NAFLD, using liver biopsy as the reference standard. Consecutive patients with a clinical indication for liver biopsy assessment of NAFLD are enrolled in this non-inferiority study. They undergo both a liver US and a multiparametric unenhanced liver MR examination. As reference standard, histological diagnosis of fibrosis and steatohepatitis made according to the fatty liver inhibition of progression (FLIP) algorithm is used. Sensitivity and specificity of imaging parameters alone or in different combinations will be calculated with the aim of finding one or more tests with at least 90% sensitivity/specificity compared to liver biopsy.

Description:

The estimated overall global prevalence of non-alcoholic fatty liver disease (NAFLD) is around 25% and projected at 33.5% in 2030. While simple steatosis without evidence of inflammation and hepatocellular injury (non-alcoholic fatty liver) is generally a benign condition, non-alcoholic steatohepatitis (NASH) can progress to fibrosis, cirrhosis, liver failure and hepatocellular carcinoma. Since only histological analysis can accurately evaluate NAFLD patterns, liver biopsy is the gold standard for assessment, and it should be considered in patients who are at increased risk of having steatohepatitis and/or fibrosis. Major drawbacks are its invasive nature, risk of complications, sampling errors and inter and intra-observer variability. Currently, there are no approved therapies for NASH. However, several drugs are now in phase 2 and 3 trials, and results are expected in 1-2 years. If medical treatments become available, screening for steatohepatitis and fibrosis will be recommended in high-risk patients. The lack of non-invasive tools to identify patients who may benefit from a therapeutic intervention is a central issue. Should liver biopsy be avoided or reserved for a more limited number of undetermined or high-risk patients, the benefit-harm balance of NASH screening and therapies would undergo a major change. Some imaging methods, mostly ultrasound (US) or Magnetic Resonance (MR) techniques, have shown promising potential in fibrosis and NASH diagnosis. The objective of this study is to evaluate the diagnostic accuracy of non-invasive imaging techniques including US and MR methods, in diagnosing NASH and fibrosis in patients with or at high risk of NAFLD, using liver biopsy as the reference standard. Consecutive patients with a clinical indication for liver biopsy assessment of NAFLD are enrolled in this non-inferiority study. They undergo both a liver ultrasound (US), including shear wave elastography (SWE) with liver stiffness measurement and US- fatty liver index (US-FLI), and a multiparametric unenhanced liver magnetic resonance examination including MR spectroscopy (MRS), Proton Density Fat Fraction (PDFF) and T2* measurement with Multiecho technique, T1 mapping with Inversion Recovery method, and Intravoxel Incoherent Motion diffusion weighted imaging (IVIM-DWI), measuring different parameters. As reference standard, histological diagnosis of fibrosis and steatohepatitis made according to the fatty liver inhibition of progression (FLIP) algorithm is used. Sensitivity and specificity of imaging parameters alone or in different combinations will be calculated, with the aim of finding one or more tests with at least 90% sensitivity/specificity compared to liver biopsy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: June 1, 2022
• Est. primary completion date: January 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• clinical indication to perform a liver biospy for NAFLD assessment based on all of the

following:

1. presence of liver steatosi at ultrasound

2. at least one risk factor for NASH/fibrosis (obesity, or type 2 diabetes mellitus, or metabolic syndrome)

3. increased liver enzymes (at least one of: GOT>40 U/l, GPT>49 U/l, GGT>75 U/l) or high NAFLD fibrosis score (>0.675), or intermediate NAFLD fibrosis score (between -1.455 and 0.675) and increased liver stiffness at transient elastography (>7 KPa).

• consent to participate in the study

Exclusion Criteria:

• age < 18 years
• secondary causes of liver steatosis (moderate to severe alcohol consumption, steatogenic drugs)
• known diffuse liver diseases other than NAFLD (cirrhosis, viral or autoimmune hepatitis, hemochromatosis, amiloidosis, other) or previous primary or secondary liver neoplasms
• contraindications to perform liver biopsy (ascites, platelet count<50.000/mmc, INR>1.5, PT>50%, serum bilirubin >3 mg/dL)
• contraindications to perform magnetic resonance (pace-maker, claustrophobia, pregnancy, MR-unsafe metallic implants)

Related Conditions & MeSH terms

• Fatty Liver
• Fibrosis
• Liver Cirrhosis
• Liver Diseases
• Liver Fibroses
• Non-Alcoholic Fatty Liver Disease
• Steatohepatitis, Nonalcoholic

Intervention

Diagnostic Test:
• Ultrasound and Magnetic Resonance
liver ultrasound (US), including shear wave elastography (SWE) with liver stiffness measurement and US- fatty liver indicator (US-FLI), and a multiparametric unenhanced liver magnetic resonance examination including MR spectroscopy (MRS), Proton Density Fat Fraction (PDFF) and T2* measurement with Multiecho technique, T1 mapping with Inversion Recovery method, and Intravoxel Incoherent Motion diffusion weighted imaging (IVIM-DWI), measuring different parameters.

Locations

Country	Name	City	State
Italy	Azienda USL-IRCCS di Reggio Emilia	Reggio Emilia	RE

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Unità Sanitaria Locale Reggio Emilia

Country where clinical trial is conducted

Italy, 

References & Publications (11)

Ballestri S, Lonardo A, Romagnoli D, Carulli L, Losi L, Day CP, Loria P. Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD. Liver Int. 2012 Sep;32(8):1242-52. doi: 10.1111/j.1478-3231.2012.02804.x. Epub 2012 Apr 22. — View Citation

Bedossa P; FLIP Pathology Consortium. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology. 2014 Aug;60(2):565-75. doi: 10.1002/hep.27173. Epub 2014 Jun 26. — View Citation

Besutti G, Valenti L, Ligabue G, Bassi MC, Pattacini P, Guaraldi G, Giorgi Rossi P. Accuracy of imaging methods for steatohepatitis diagnosis in non-alcoholic fatty liver disease patients: A systematic review. Liver Int. 2019 Aug;39(8):1521-1534. doi: 10.1111/liv.14118. Epub 2019 May 8. — View Citation

Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-357. doi: 10.1002/hep.29367. Epub 2017 Sep 29. Review. — View Citation

Eddowes PJ, McDonald N, Davies N, Semple SIK, Kendall TJ, Hodson J, Newsome PN, Flintham RB, Wesolowski R, Blake L, Duarte RV, Kelly CJ, Herlihy AH, Kelly MD, Olliff SP, Hübscher SG, Fallowfield JA, Hirschfield GM. Utility and cost evaluation of multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2018 Mar;47(5):631-644. doi: 10.1111/apt.14469. Epub 2017 Dec 22. — View Citation

Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018 Jan;67(1):123-133. doi: 10.1002/hep.29466. Epub 2017 Dec 1. Review. — View 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. J Hepatol. 2016 Jun;64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004. Epub 2016 Apr 7. — View Citation

Issa D, Patel V, Sanyal AJ. Future therapy for non-alcoholic fatty liver disease. Liver Int. 2018 Feb;38 Suppl 1:56-63. doi: 10.1111/liv.13676. Review. — View Citation

Park CC, Nguyen P, Hernandez C, Bettencourt R, Ramirez K, Fortney L, Hooker J, Sy E, Savides MT, Alquiraish MH, Valasek MA, Rizo E, Richards L, Brenner D, Sirlin CB, Loomba R. Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease. Gastroenterology. 2017 Feb;152(3):598-607.e2. doi: 10.1053/j.gastro.2016.10.026. Epub 2016 Oct 27. — View Citation

Pavlides M, Banerjee R, Tunnicliffe EM, Kelly C, Collier J, Wang LM, Fleming KA, Cobbold JF, Robson MD, Neubauer S, Barnes E. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. Liver Int. 2017 Jul;37(7):1065-1073. doi: 10.1111/liv.13284. Epub 2017 May 30. — View Citation

Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014 Jan 14;20(2):475-85. doi: 10.3748/wjg.v20.i2.475. Review. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	False positives	false positives of each imaging parameter compared to liver biopsy in the diagnosis of NASH/fibrosis	baseline
Primary	False negatives	false negatives of each imaging parameter compared to liver biopsy in the diagnosis of NASH/fibrosis	baseline
Primary	Sensitivity	Sensitivity of each imaging parameter compared to liver biopsy in the diagnosis of NASH/fibrosis	baseline
Primary	Specificity	Specificity of each imaging parameter compared to liver biopsy in the diagnosis of NASH/fibrosis	baseline
Secondary	Correlation of quantitative imaging parameters with histopathological, demographic, anthropometric and clinical characteristics	Correlation of imaging parameters (US-FLI, US-SWE, MR-PDFF, MR-T1, MR-T2*, MR-IVIM coefficients, MRS metabolites) with histopathological (percentage of steatosis, lobular inflammation, hepatocellular ballooning, fibrosis), demographic (age, sex), anthropometric (BMI, waist circumference) and clinical (liver enzymes, NAFLD fibrosis score, FIB4) characteristics	baseline
Secondary	Number of patients whit incomplete or unreliable imaging tests		baseline