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


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

In This Article


Main Findings

We demonstrated that liver stiffness by MRE was an independent predictor for the presence of CAC in a well-characterised NAFLD cohort using both sex and age-, and FRS-adjusted analysis. For patients with NAFLD, significant fibrosis (defined by MRE-stiffness ≥2.97 kPa) was an also independent predictor for the presence of CAC. In addition, CAC was more prevalent in patients with significant fibrosis.

These findings demonstrate that patients with NAFLD and significant fibrosis are at higher risk for CVD regardless of their traditionally classified risk of CVD. NAFLD is prevalent in one fourth of the global population. However, traditional CVD risk scores, such as FRS, may not be sufficient to fully assess CVD risk in this population, because they do not take NAFLD into account. Thus, MRE may benefit patients with NAFLD by helping to predict their risk of CVD.

In Context With Published Literature

The association between NAFLD and CAC has been reported in several cohort studies.[21–24] Most of these studies have demonstrated that NAFLD is an independent risk factor among the traditional risk factors.[21–23] A recent study demonstrated the association of both NAFLD and alcoholic fatty liver disease with CAC in young and middle-aged populations.[23] While this study also demonstrated an association between NAFLD severity, based on FIB-4, and CAC, their results had limited power as very few subjects had advanced fibrosis.[23]

The association between hepatic fibrosis and the risk of CVD in patients with NAFLD has been reported in several studies.[9,11,25–28] NASH-related fibrosis is associated with increased small dense low-density lipoprotein and oxidised phospholipids leading to oxidative stress and mitochondrial damage, which may also increase the risk of atherosclerosis.[29,30] Neutralisation of these oxidised phospholipids leads to resolution of NASH as well as reduction of atherosclerosis.[30] Most clinical studies have demonstrated this association using non-invasive assessment for fibrosis based on indirect serum biomarkers, such as NFS and FIB-4 index.[25,26] Only a few studies have demonstrated an association of hepatic fibrosis with the risk of CVD in patients with biopsy-proven NAFLD.[9,11,27] To the best of our knowledge, this is the first study to evaluate the association of CAC with MRE-determined liver stiffness in patients with NAFLD. Unlike other studies,[9,11,25,26] which have demonstrated the association between advanced (stage ≥3) fibrosis and the risk of CVD, we found that significant (stage ≥2) fibrosis associated with CAC. As the presence of CAC, a highly specific feature of subclinical coronary atherosclerosis, is associated with subclinical CVD,[31] we believe that the presence of CAC is associated with significant fibrosis rather than advanced fibrosis. Traditional CVD risk-scoring models include established CVD risk factors such as age, sex, body mass index, race, smoking status, hypertension, diabetes and dyslipidaemia and predict the 10-year risk of CVD.[7,8] When traditional risk-scoring models lead to unclear results, cardiac CT for CAC is considered to assist treatment decisions.[7] The presence of CAC is known to be associated with an increased risk for CVD in many cohort studies.[31] In this study, the prevalence of CAC was approximately 25% higher in patients with significant fibrosis compared to those without. Thus, we believe that MRE in patients with NAFLD may help reduce the burden of radiation exposure from a cardiac CT scan for CAC.

Strengths and Limitations

The strengths of this study are as follows: first, this is a cross-sectional study derived from two well-characterised prospective cohorts. Second, unlike previous studies, NAFLD and liver stiffness were defined by MRI-PDFF and MRE, which are among the most reliable non-invasive modalities for assessment of hepatic steatosis and liver fibrosis, respectively. Previous studies using liver biopsy have shown limitations for diagnosing significant fibrosis due to inter- and intra-observer variability. Thus, this study provides new evidence of clinical significance regarding the risk of CVD in patients with NAFLD and significant fibrosis.

However, there are several limitations in this study. First, this is a single-centre study with a relatively small number of patients. Therefore, a large-scale, longitudinal study is needed to validate the findings. Second, to our knowledge, no other study has investigated the association between significant fibrosis, as defined by MRE > 2.97 kPa, and CAC. Thus, we were unable to perform a power analysis. Third, since a subset of the patients analysed in this study had been diagnosed with NAFLD and referred for clinical trial participation, this study had relatively higher proportion of patients with severe NASH compared to a random, general population. In addition, different sets of eligibility criteria from the two contributing studies could have contributed to selection bias. Therefore, further validations from the general population are needed.