Cardiovascular Risk Underestimated in Women With NAFLD

By Marilynn Larkin

October 17, 2019

NEW YORK (Reuters Health) - Women with nonalcoholic fatty liver disease (NAFLD) lose the cardiovascular protection conferred by female sex, and so their risk of cardiovascular events is underestimated, researchers say.

"The main finding in this population is that NAFLD has distinct consequences in women compared to men." Dr. Alina Allen of Mayo Clinic in Rochester, Minnesota told Reuters Health by email. "Specifically, women with NAFLD lose the protection normally associated with the female sex. In consequence, the excess mortality and cardiovascular disease, such as heart attacks and strokes, between those with and without NAFLD is much higher in women than men at all ages."

"Surprisingly," she added, "we found that the risk calculators commonly used by physicians underestimate cardiovascular risk in those with NAFLD, especially in women. These findings are important because they can impact timely initiation of aspirin and statins."

As reported online October 2 in the American Journal of Gastroenterology, Dr. Allen and colleagues identified 3,869 adults diagnosed with NAFLD in Olmsted County, Minnesota, between 1997 and 2014, and 15,209 age- and sex-matched controls from the general population.

During follow-up for a median of seven years, 3,851 cardiovascular events were recorded.

Female sex was protective against ischemic cardiovascular events in the control group (hazard ratio, 0.71), but the impact was significantly attenuated among those with NAFLD (HR, 0.90).

The findings held true even after stratification by time-dependent cardiovascular risk factors (e.g., diabetes, smoking, hypertension, dyslipidemia) and - as a surrogate for access to care - after controlling for diagnostic testing (liver enzymes and ultrasound) during routine medical evaluations.

As Dr. Allen noted, overall, excess events were higher in women than in men with NAFLD - cardiovascular disease (18% vs. 9%) and mortality (9% vs. 6%).

Given the diminished protection for women, the team also assessed the performance of the pooled cohort equations (PCEs) on the 10-year atherosclerotic cardiovascular disease risk prediction (heart attack or stroke). They found "the current PCEs consistently underestimate the 10-year risk of myocardial infarction or stroke in NAFLD women, across all risk strata, whereas they overestimate the CV risk in those without NAFLD."

The authors conclude, "As CV morbidity represents a significant burden in NAFLD, underestimating risk may have significant public health consequences, impacting half of the NAFLD population or approximately 40 million women in the country."

Dr. Allen said, "We hope to increase the awareness of healthcare teams that NAFLD patients may benefit from prevention at lower than conventional thresholds. Shared-decision making should take NAFLD into consideration as an important comorbidity. Efforts should continue to produce accurate tools to estimate risk of cardiovascular disease in this high-risk group."

Dr. Michelle O'Donoghue, a senior investigator in the TIMI Study Group at Brigham and Women's Hospital in Boston, called the analysis "interesting."

"Although the authors tried to take into account baseline differences, it is notable that the women with NAFLD had more cardiovascular risk factors when compared to men with NAFLD," she said in an email to Reuters Health. "The same findings were not observed in individuals without NAFLD, (which) raises the possibility that the observed findings are explained by other risk factors that travel along with having a fatty liver."

"For that reason," she noted, "one cannot be sure that the presence of a fatty liver obviates any protective effects of female sex on the risk of heart disease."

"Regardless, there remain some very important messages," she said. "We know that several traditional risk factors such as obesity, diabetes and high cholesterol, increase a person's risk of developing a fatty liver. We don't know with certainty if a fatty liver by itself increases the risk for heart disease, but it is likely an excellent reflector of overall metabolic health."

"Until better risk scores are developed, I absolutely agree that the presence of a fatty liver should be considered a 'red flag' for any physician, regardless of a patient's calculated risk, and appropriate counseling or treatment should be offered," she concluded.


Am J Gastroenterol 2019.