Liver Stiffness by Magnetic Resonance Elastography Is Associated With Increased Risk of Cardiovascular Disease in Patients With Non-alcoholic Fatty Liver Disease

Jung Gil Park; Jinho Jung; Kritin K. Verma; Min Kyu Kang; Egbert Madamba; Scarlett Lopez; Aed Qas Yonan; Amy Liu; Ricki Bettencourt; Claude Sirlin; Rohit Loomba

Disclosures

Aliment Pharmacol Ther. 2021;53(9):1030-1037. 

In This Article

Methods

Study Design and Data Collection

This was a cross-sectional analysis of a single-centre study from two previous studies of adults with type 2 diabetes ("Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE") or non-alcoholic steatohepatitis (NASH, Magnetic resonance imaging and elastography in ezetimibe versus placebo for the assessment of response to treatment in NASH trial, Figure S1).[16,17] All participants were prospectively recruited at the University of California at San Diego (UCSD) NAFLD Research Center from January 2013 to August 2014. A research study visit included demographics, anthropometric measurements, physical examination, biochemical testing, coronary calcium scan, MRE and magnetic resonance image-derived proton density fat fraction (MRI-PDFF). The eligibility criteria for the two studies are described in previous publications.[16,17] Main exclusion criteria were as follows: non-NAFLD chronic liver diseases, steatogenic medications, significant systemic illness, renal insufficiency, excessive alcohol use, human immunodeficiency virus, pregnancy, documented history of CVD, such as acute coronary syndrome (ST elevation myocardial infarction, non-ST elevation myocardial infarction, unstable angina), stable angina, history of angioplasty or stent placement, cerebrovascular disease (ischaemic or haemorrhagic stroke), and peripheral vascular disease for type 2 diabetes study,[17] and significant coronary artery disease for NASH study.[16] The studies received UCSD institutional review board approval (approval numbers: UCSD IRB #121508 and #121314) and all patients provided written informed consent prior to enrolment.

Non-invasive fibrosis scores such as the NFS and FIB-4 index were calculated and categorised accordingly.[18,19] The FRS was calculated using the algorithm from a previous publication.[8] Homoeostatic model assessment of insulin resistance (HOMA-IR) was calculated using the following formula:

Adipose tissue IR (Adipo-IR) was calculated using the following formula:

Both insulin resistance tests underwent in a fasting state.

Primary and Secondary Outcome

The primary outcome of the study was defined as the presence of CAC in patients with NAFLD, as defined by MRI-PDFF ≥ 5%. The secondary outcome of the study was defined as the prevalence of CAC in patients with NAFLD and significant fibrosis, as defined by MRE-stiffness ≥ 2.97 kPa.

MRE and MRI-PDFF

All MR examinations were performed by the UCSD Liver Imaging Group at the MR3T Research laboratory using a 3T research scanner (GE Signa EXCITE HDxt; GE Healthcare). Trained and experienced MR technologists performed all the MR examinations. Patients were instructed to fast for a minimum of 4 hours before the MR scan to reduce potential physiological confounding factors. A torso phased-array coil was placed over the abdomen as the patient lay supine during imaging. Two MR techniques were utilised in the study: for NAFLD diagnosis, hepatic PDFF was estimated by chemical-shift-encoded MRI; for liver fibrosis assessment and diagnosis of significant fibrosis, hepatic stiffness was estimated by MRE. Significant fibrosis was defined as MRE-stiffness ≥ 2.97 kPa in accordance with a previous published study.[14] Trained image analysts, under the supervision of a faculty radiologist, performed the PDFF and stiffness measurements while blinded to clinical and biochemical data.

Cardiac Computed Tomography for CAC

A non-contrast cardiac prospective electrocardiogram-triggered volumetric computed tomography (CT) was performed using a 320-slice CT scanner (Aquilion One, Toshiba Medical Systems). No administered medications for heart rate control or vasodilation were administered before the scan. At the end of inspiration, the patient held their breath as the scan ranged from the base of the heart to the carina; the field of view was 220 mm while the scan collimation was 320 × 0.5 mm. As determined by the SUREExposure 3D scanner software, a tube current ranging from 40 to 580 mA (±10) at 120 kVp was administered. Rotation time was 0.35 seconds. Using five filter revolutions, 3-mm thick reconstruction slices were made. The Agatston scoring method, previously described by a fellowship-trained cardiac radiologist using independent post-processing software (Vital Images, Inc.),[20] was used to quantify CAC. The presence of CAC was defined as coronary artery calcium score >0.

Statistical Analysis

Continuous data were shown with a mean and standard deviation (mean ± SD) or median with interquartile range. Continuous data were compared using Student's t-test or the Mann-Whitney U test after Shapiro-Wilk normality testing. Categorical data were compared by a chi-squared test or Fisher's exact test when more than 20% of cells expected frequencies below 5. The predictive factors for the presence of CAC were analysed by a logistic regression model with stepwise backward elimination for odds ratio (OR). All statistical analyses were performed using R software (version 3.0, http://cran.r-project.org/, install.packages("devtools")). Logistic regression model-based plotting for probability of the presence of CAC was generated using ggplot2. A two tailed P ≤ 0.05 was used to determine statistical significance.

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