Risk of Cardiovascular Disease in Individuals With Nonobese Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is independently associated with obesity and cardiovascular disease (CVD).CVD is the primary cause of mortality in the predominantly obese population of adults with NAFLD. NAFLD is increasingly seen in individuals who are lean and overweight (i.e., nonobese), but it is unclear whether their risk of CVD is comparable to those with NAFLD and obesity. Using a prospective cohort of patients with NAFLD, we compared the prevalence and incidence of CVD in individuals with and without obesity. NAFLD was diagnosed by biopsy or imaging after excluding other chronic liver disease etiologies. Logistic regression was used to compare the odds of baseline CVD by obesity status. Cox proportional hazards regression was used to evaluate obesity as a predictor of incident CVD and to identify predictors of CVD in subjects with and without obesity. At baseline, adults with obesity had a higher prevalence of CVD compared to those without obesity (12.0% vs. 5.0%, P = 0.02). During follow-up, however, obesity did not predict incident CVD (hazard ratio [HR], 1.24; 95% confidence interval [CI], 0.69-2.22) or other metabolic diseases. Findings were consistent when considering body mass index as a continuous variable and after excluding subjects who were overweight. Age (adjusted HR [aHR], 1.05; 95% CI, 1.03-1.08), smoking (aHR, 4.61; 95% CI, 1.89-11.22), and decreased low-density lipoprotein levels (aHR, 0.98; 95% CI, 0.96-1.00) independently predicted incident CVD in the entire cohort, in subjects with obesity, and in those without obesity, respectively. Conclusion: Individuals with overweight or lean NAFLD are not protected from incident CVD compared to those with NAFLD and obesity, although CVD predictors appear to vary between these groups. Patients without obesity also should undergo rigorous risk stratification and treatment. (Hepatology Communications 2021;0:1-11). N onalcoholic fatty liver disease (NAFLD)is the most prevalent chronic liver disease worldwide, impacting an estimated 25% of the global population and incurring a cost of more than $100 billion per annum in the United States alone. (1,2) NAFLD is projected to continue increasing in prevalence during the next decade. (3) NAFLD is an independent risk factor for cardiovascular disease (CVD) and major adverse CVD events. (4) CVD is a leading cause of mortality in this population, (5)

Higher mortality among lean patients with non‐alcoholic fatty liver disease despite fewer metabolic comorbidities

“…A prospective cohort study from United States with 394 NAFLD patients (diagnosed with ultrasound or histology) with a median follow-up of 5.7 years also found no significant difference in incidence of CVD between obese versus non-obese patients with NAFLD. 34 In contrast, a recent study from the Olmsted county database and a multicentre-study from four countries (Italy, United Kingdom, Spain and Australia) showed no significant differences in the incidence of both liver and non-liver events: cirrhosis, liverrelated events/decompensation, DM and CVD between lean and obese subjects with NAFLD. 5,12 Non-invasive fibrosis scores such as FIB-4 have been proposed to risk stratify patients with NAFLD for liver-related outcomes.…”

“…In our longitudinal analysis, we found a lower incidence of cirrhosis and DM among lean individuals with NAFLD compared to overweight/obese individuals with NAFLD with no significant differences in incident CVD, all cancers or obesity‐related cancers. A prospective cohort study from United States with 394 NAFLD patients (diagnosed with ultrasound or histology) with a median follow‐up of 5.7 years also found no significant difference in incidence of CVD between obese versus non‐obese patients with NAFLD 34 . In contrast, a recent study from the Olmsted county database and a multicentre‐study from four countries (Italy, United Kingdom, Spain and Australia) showed no significant differences in the incidence of both liver and non‐liver events: cirrhosis, liver‐related events/decompensation, DM and CVD between lean and obese subjects with NAFLD 5,12 .…”

Risk of cardiovascular disease in lean patients with nonalcoholic fatty liver disease

“…In particular, reports comparing the CVD incidence between lean and non-lean NAFLD are limited. A study that primarily included Hispanics (40.8% of whom had NAFLD without obesity) in the United States reported no signi cant difference in the incidence of new CVD between the lean and non-lean NAFLD groups (30).…”

Mechanisms of non-alcoholic fatty liver disease development in normal-weight individuals

“…For this situation, particularly lean individuals with comorbid conditions should be examined to rule out liver involvement, mainly for individuals older than 40 with type 2 diabetes [13]. Notably, it has also been observed that individuals with NAFLD and normal weight have a risk of developing atherosclerotic cardiovascular disease similar to that of obese patients with NAFLD [22]. This suggests that, although the mortality rate is higher in obese NAFLD patients, having a body weight classified as normal does not confer protection against atherosclerotic cardiovascular disease in individuals with NAFLD, with men around 40 years of age and women in their 50s being the most affected [23][24][25].…”