VIENNA – As the severity of nonalcoholic fatty liver disease (NAFLD) increases, so does the risk for death and cardiovascular disease, according to data from a large population study reported at the meeting sponsored by the European Association for the Study of the Liver.

There was a 50% increase in the adjusted all-cause morality rate when comparing patients who developed nonalcoholic steatohepatitis (NASH) with those who had NAFLD (hazard ratio of 1.5).

The risk of death was also five times as high when comparing patients with NASH-related cirrhosis to those with NAFLD, with an adjusted HR of 5.1.

Heart failure (HF), atrial fibrillation (AF), type 2 diabetes mellitus, and chronic kidney disease (CKD) rates were also increased in patients with NAFLD, compared with those in the healthy population.*

“Nonalcoholic fatty liver disease has got a strong association with cardiovascular disease; it may be an independent risk factor for cardiovascular disease, but that is still open to debate,” said study investigator Dr. Jake Mann, who is an academic clinical fellow in pediatrics at the University of Cambridge (England).

“What isn’t quite so clear is whether or not there is progressively increasing risk of cardiovascular comorbidities as you move from NAFLD to NASH to NASH cirrhosis,” he added at the meeting, which was sponsored by the European Association for the Study of the Liver (EASL).

To investigate this further, Dr. Mann and collaborators therefore obtained data collected on more than 929,465 patients with NAFLD-related diseases included in the U.K. ACALM (Algorithm for Comorbidities, Associations, Length of stay, and Mortality) study database. ICD-10 codes were used to identify patients with NAFLD, NASH, cryptogenic (NASH)-cirrhosis, and cardiovascular morbidities.

During the 14-year follow-up period, 1,294 patients were diagnosed with NAFLD, 122 with NASH, and 1,285 with cirrhosis. Around 57% of patients in each group were male, with the mean age rising from 50.6 years in the NAFLD patients to 51.6% in the NASH patients to 59.2% in the patients with cirrhosis. Most (76%-80%) patients were white, with around 10%-12% being of Asian ethnicity.

HF was more prevalent in patients with NASH (9% vs. 3.8%, P < .01) and cirrhosis (6.6% vs. 3.8%; P < .001) than in those with NAFLD. The prevalence of AF was increased progressing from NAFLD to NASH (4.9% vs. 8.2%) and NAFLD to cirrhosis (4.9% vs. 8.3%; P < .0001). Rates for diabetes were 20.9%, 24.6%, and 31.2% and for CKD were 2.1%, 4.9%, and 6.9% progressing from NAFLD to NASH to cirrhosis.

Hyperlipidemia and hypertension rates for NAFLD, NASH, and cirrhosis were 12.1%, 17.2%, and 5%, and 29.4%, 34.4%, and 27.3%, respectively.

Crude mortality rates were 11.5% for the general population and 14.5% for NAFLD, 22.1% for NASH, and 53.1% for cirrhosis. “Unfortunately we do not have disease-specific mortality data,” Dr. Mann said.

There are of course several limitations that need consideration, including assuming NASH was a biopsy-proven diagnosis. The findings are also reliant on data coding and of course it is possible that patients with NASH are included in the NAFLD group, and non-NASH cirrhosis could be included in the cryptogenic cirrhosis group.

There is also the chance of underdiagnosis and undercoding, Dr. Mann said. The overall prevalence of NAFLD-spectrum disease was 2.5%, which is perhaps somewhat lower than might be expected in a large U.K. population.

Other limiting factors were that the patients with the cryptogenic cirrhosis group were older than those in the other groups and also that these findings could be describing the natural history of the disease rather than implying causation.

Nevertheless, this is the largest study of its kind, Dr. Mann said, and shows that there is a trend towards increasing mortality and burden of CVD with increasing severity of NAFLD-spectrum disease.

“The take-home message is that clinicians should be very aware of this association, such that hepatologists should consider that patients are at very high risk of heart disease, and as they currently do, they should screen for cardiovascular disease and refer on as appropriate,” Dr. Mann said in an interview.

“Likewise, cardiologists and general practitioners should be very aware that patients with cardiac disease are at risk of NAFLD and equally would refer to GI and liver teams,” Dr. Mann said.

“These findings clearly link the severity of [nonalcoholic fatty liver disease] with the increased risk of cardiovascular disease and death,” Dr. Laurent Castera of Hôpital Beaujon in France said in a press release issued by the EASL.

Dr. Castera, who is the vice-secretary of the association added: “It is therefore imperative that we identify people in the early stages of [the disease] so they can be treated through diet and lifestyle interventions before their condition becomes potentially deadly.”

*A correction was made to this sentence on 5/22/2015.

EASL: Mortality and CV burden increase with NAFLD severity