Outcomes and Mortality Risks in Patients With NAFLD

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Mortality and liver-related complications increased with fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD).

As fibrosis stage increases, so does mortality for patients with nonalcoholic fatty liver disease (NAFLD). Patients with fibrosis stages F3 and F4 had increased risks of liver-related complications and death, according to a study published in New England Journal of Medicine.

NAFLD affects more than one-fourth of the adult population worldwide, and in addition to being linked to a variety of disorders, such as obesity and type 2 diabetes, it is a growing contributor to end-stage liver disease and the need for a liver transplant. However, knowledge of NAFLD-related prognoses is limited.

“The true rates and types of clinical outcomes among persons with nonalcoholic fatty liver or NASH [nonalcoholic steatohepatitis] with varying grades of disease activity and fibrosis stages thus remain largely unknown,” the authors explained. “This knowledge is needed in order to counsel patients, design clinical trials, and inform allocation of health care resources for research funding, clinical care, and disease surveillance.”

The NAFLD Database Study Phase 2 included adults who had liver biopsies that revealed NAFLD and had at least 1 follow-up after 48 weeks. It is a prospective, noninterventional registry of the NASH Clinical Research Network, which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases.


There were 1773 patients included in the analysis, with a median follow-up duration of 4.0 years. Compared with patients who had no follow-up data and were excluded from the analysis, the patients with follow-up data tended to be older at enrollment, were more likely to be women, and were taking more antihypertensive medication.

The majority of patients in the analysis were women (64%), and the mean age of the overall cohort was 52 years. The majority of patients were White and of European ancestry (85%). Slightly more than half 55%) had definite steatohepatitis, 20% had borderline steatohepatitis, and 25% had fatty liver without NASH. Thirty percent had bridging fibrosis (stage F3) or cirrhosis (stage F4).

At baseline, 61% of patients had hypertension, 42% had diabetes, 10% had previous nonhepatic primary cancer, 6% had chronic kidney disease (CKD), and 6% had a history of a cardiac event. Patients with stage F4 fibrosis had a greater prevalence of liver-related outcomes, hypertension, CKD, and cardiac events at baseline compared with patients with stage F0 to F2 fibrosis.

A total of 47 (3%) patients died during follow-up, while 37 patients had a new-onset decompensation event. The most common nonhepatic outcome was new-onset hypertension. Patients with hepatic decompensation before enrollment had the highest mortality, and patients who had a history of 2 or more events before enrollment had the highest incidence of death.

At stages F- to F2 all-cause mortality was 0.32 deaths per 100 person-years, which increased to 0.89 deaths at stage F3 and to 1.76 deaths at stage F4. Compared with patients who had stage F0 to F2 fibrosis, patients with stage F4 had higher all-cause mortality (HR, 3.9; 95% CI, 1.8-8.4) and liver-related mortality was also higher for patients with stage F4 disease (HR, 12.7; 95% CI, 1.8-88.6).

Incidence of hepatocellular carcinoma was rare among patients with stage F0 to F2 (0.04 events per 100 person-years) and was higher in stage F3 (0.34 events) vs stage F4 (0.14 events). In addition, 93% of patients with stage 4 fibrosis and 97% with stage F3 had evidence of definite or borderline NASH.

One of the limitations of the study was that the cohort was predominantly White and people of Hispanic ancestry were underrepresented in the study population.

The authors noted that their findings “provide support for the use of ‘progression to cirrhosis’ as a generally accepted surrogate outcome for regulatory approval of therapeutic agents.”


Sanyal AJ, Van Natta ML, Clark J, et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med. 2021;385(17):1559-1569. doi:10.1056/NEJMoa2029349