Synopsis

Vendor-certified proton density fat fraction (PDFF) sequences are commercially available across multiple scanner systems and represent a robust method for quantification of liver fat and liver T2* mapping. Type 2 diabetes mellitus (T2DM) is associated with non-alcoholic fatty liver disease and dysregulation of iron homeostasis. Duodenal mucosal resurfacing (DMR) is a novel treatment for patients with T2DM who have poor glycaemic control. We describe our technique for quality assurance across multiple sites using custom fat-water phantoms and report preliminary liver PDFF and liver iron concentration results from a cross-site, multi-vendor study in patients at baseline and 12 weeks after DMR.

Introduction

MRI-based proton density fat fraction (PDFF) has established its potential as a non-invasive, quantitative and accurate liver fat content trial endpoint.¹ The accuracy of PDFF derived liver fat fraction (FF) measurements is reliant on correction for T2*-related signal decay.² PDFF sequences therefore also generate T2* maps, which are used to estimate liver iron concentration (LIC).³ Vendor-derived PDFF sequences (e.g. Philips mDixonQuant, GE IDEAL-IQ) enable multi-site, multi-vendor, multi-field strength studies. Phantom-based quality assurance (QA) is required to ensure baseline coherence and longitudinal stability of measurements.

Type 2 diabetes mellitus (T2DM) prevalence is rising with approximately 382 million people affected globally in 2017.⁴ T2DM is characterised by insulin resistance in target organs and associated with non-alcoholic fatty liver disease (NAFLD) and dysregulation of iron homeostasis. As the liver represents an important site for glucose and iron metabolism, treatment of T2DM is thought to be associated with reductions in liver fat and liver iron content.⁵

Current treatments for T2DM include lifestyle modification, anti-diabetic medications and bariatric surgery; however, a growing number of patients have persistent poor glycaemic control. Duodenal mucosal resurfacing (DMR) is a novel endoscopic procedure in which the duodenum is ablated using a specially-designed catheter, with early data demonstrating improvements in glycaemic control in patients with T2DM.⁶

Revita-2, is a phase-II blinded, sham-controlled, international multi-site, multi-vendor cross-over trial (NCT02879383) designed to evaluate the effects of DMR on glycaemic control and liver FF and LIC using MRI-PDFF in patients with T2DM. Each of the study sites completed up to 5 training (non-randomised) cases to familiarise themselves with the procedure prior to randomisation. We utilised a custom-built liquid emulsion-based QA phantom and report preliminary baseline and 12-week post-treatment PDFF results from the non-randomised cohort.

Methods

Data were acquired at 6 scanning sites (3 Phillips 3T systems; 1 GE 3T system; 2 GE 1.5 systems).

Phantom QA studies:

Six identical fat-water liquid-emulsion based QA phantoms were constructed using known concentrations of peanut oil and 0.008% carrageenan solution, covering a range of PDFF values (Figure 1a,b). Baseline scans were performed centrally on a Phillips 3T Ingenia system (acquisition parameters Figure 2a). Each site performed an initial assessment scan of their phantom locally and at 6 monthly intervals with specified acquisition parameters (Figure 2b). All scans were reviewed to ensure compliance with acquisition parameters.

Circular regions of interest (ROIs) were placed on PDFF maps for each tube (Figure 1c). Measured and reference PDFF values were compared using linear regression (Figure 3a). Central and local baseline scans of each phantom and subsequent interval QA scans were compared using Bland-Altman limits of agreement (Figure 3b).

Patient studies:

T2DM patients (n=20) were recruited prospectively as per trial inclusion criteria. Subjects underwent MRI-PDFF of the liver at baseline and 12 weeks following DMR treatment using specified acquisition parameters (Figure 2b).

Studies were analysed using a custom online platform (Ambra Health, New York, USA). A circular ROI measuring up to 20mm² in diameter was placed in each of the 9 Coinaud liver segments colocalised on PDFF maps and T2* maps, avoiding vessels and the biliary tree (Figure 4a).

LIC (μmol/g) was estimated from T2* data based on previously published methods.³

Absolute and relative (% of baseline) within-subject change in liver FF and LIC were assessed using the t-test.

Results

Reference and measured phantom FF were correlated for all sites (r2=0.997, p<0.0001), Figure 3a. Bland-Altman 95% limits of agreement for baseline and 12-week PDFF were 0.57±3.53% (Figure 3b).

All liver segments demonstrated statistically significant reductions in FF (p<0.05, Figures 4b,5a,b), with an average 12-week reduction across all liver segments in absolute FF of -5.9% (p=0.008) and relative FF of -28.2% (p=0.002).

The average 12 week change in absolute and relative LIC across all liver segments (Figure 5c,d) was -0.87μmol/g (p=0.1197) and -2.8% (p=0.3729) respectively.

Conclusions

We demonstrate use of MRI-PDFF-derived liver FF and LIC as trial endpoints in a multi-site, multi-vendor, multi-field strength study. QA phantom measurements demonstrated good coherence with reference measurements and stability over a 6-month period.

MRI-PDFF demonstrated statistically significant changes in absolute and relative liver FF in a cohort of 20 patients 12 weeks after DMR. Reduction in liver fat deposition may lead to reduced insulin resistance and improve hepatic glucose metabolism. Further longitudinal assessment of liver FF in this cohort will enable analysis of change over a longer time period and appraise the potential for sustained reductions in liver FF.

There was no significant change in LIC 12 weeks after DMR. We plan to make further longitudinal assessments of LIC in this cohort and correlate with biochemical markers of diabetes.

Acknowledgements

References

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