Advanced Fibrosis Tied to Most Severe Outcomes in NAFLD

In patients with non-alcoholic fatty liver disease (NAFLD), advanced fibrosis was associated with a greater risk for liver decompensation and all-cause mortality compared to those with lower stages of fibrosis, a prospective cohort study found.

In the analysis involving over 1,700 NAFLD patients, the rate of death per 100 person-years was 1.76 among those with cirrhosis (stage F4), as compared to 0.32 for those with stages F0-F2 fibrosis (HR 3.9, 95% CI 1.8-8.4), reported Arun Sanyal, MD, of the Virginia Commonwealth University School of Medicine in Richmond, and colleagues.

Patients with bridging fibrosis (stage F3) had an all-cause mortality rate of 0.89 per 100 person-years (HR 1.9 vs F0-F2, 95% CI 0.9-3.7).

"[NAFLD] affects more than one quarter of the adult population globally and is closely linked to underlying obesity, type 2 diabetes, and related disorders," the group wrote in the New England Journal of Medicine. "Its clinical and histologic spectrum ranges from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH). NAFLD is a growing contributor to the burden of end-stage liver disease and the need for liver transplantation."

In their study, the researchers found that as fibrosis increased in severity (F0-F2, F3, and F4), various liver complications tended to increase as well, including liver cancer (0.04, 0.34, and 0.14, respectively, per 100 person-years), variceal hemorrhage (0.00, 0.06, 0.70), encephalopathy (0.02, 0.75, 2.39), and ascites (0.04, 0.52, 1.20).

Models adjusting for demographics, baseline histology, and diabetes showed higher all-cause mortality associated with any liver decompensation event (adjusted HR 6.8, 95% CI 2.2-21.3).

"Approximately 14% of patients with stage F0 to F2 fibrosis have progression to stage F3, and 2% have progression to stage F4 over a mean duration of 4.5 years," they wrote. "Integration of these data with the observed outcomes translates to 15,000 additional [U.S.] deaths annually among persons whose disease transitions to stage F3 or F4."

Knowing that, patients with more advanced fibrosis need to be monitored more closely, David E. Bernstein, MD, of Northwell Health in Manhasset, New York, told MedPage Today.

This "important" paper highlights that NAFLD can progress into NASH and its associated complications, said Bernstein, who was not involved in the study. "I don't think there are any surprises, this is absolutely what we see in our practice -- those with minimal to moderate fibrosis usually do fine and those with bridging fibrosis or cirrhosis are at risk of decompensating during this time period."

This multicentered, NAFLD Database Study Phase 2 was a prospective study that evaluated 1,773 adults with NAFLD from December 2009 to April 2019. Disease was confirmed by liver biopsy. The median follow-up was 4 years. The database excludes patients with non-NAFLD liver disease, those with liver cancer prior to enrollment, and those with a prior liver transplant.

The principal outcomes assessed all-cause mortality, hepatic decompensation, Model for End-Stage Liver Disease (MELD) scores, as well as cancers and cardiac-related events.

Nearly two-thirds of the participants were women (mean age 52), 85% were white, and 12% were Hispanic. Patients had a median BMI of 33. Common comorbidities included steatohepatitis (55%), stages F3 or F4 fibrosis (30%), and borderline steatohepatitis (20%). Definitive or borderline NASH was prevalent among three-fourths of the cohort overall, but among nearly all patients who had F3 (97%) and F4 (93%) fibrosis.

Mean daily alcohol consumption was under 20 g for women and under 30 g for men. From patient biopsy to enrollment, the median time was 2.7 months.

A greater incidence of type 2 diabetes was observed among stage F4 fibrosis patients versus those with F0-F2 fibrosis (7.5 vs 4.5 events per 100 person-years, respectively), and there was a higher incidence of reduction in glomerular filtration rate of 40% or more in the F4 fibrosis group (3 vs 1 events per 100 person-years, respectively).

Incidence of non-hepatic cancers and cardiac-related events were similar across all stages of fibrosis.

The analysis had several limitations, the researchers acknowledged, including the lack of diversity among patients. Also, most data on cause of death came from unverified outside centers.

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