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Advanced fibrosis in people with NAFLD increases the risk of liver complications

Keith Alcorn
08 December 2021

Advanced liver fibrosis in people with non-alcoholic fatty liver disease was associated with an increased risk of liver-related complications, a prospective study in the United States has found.

Fat accumulation in the liver, or non-alcoholic fatty liver disease (NAFLD), affects up to a quarter of the population globally. Fat accumulation may lead to inflammation – non-alcoholic steatohepatitis (NASH) – and scarring of the liver (fibrosis). As fibrosis becomes more extensive, normal liver function declines, eventually leading to liver failure, or decompensation.

The impact of fibrosis on the health of people with NAFLD has been unclear. To understand the relationship between liver damage, liver complications and other serious health outcomes, the NASH Clinical Research Network in the United States studied a cohort of people with NAFLD who they followed for at least 48 weeks.



Improvement in a tumour. Also, a mathematical model that allows us to measure the degree to which one of more factors influence an outcome.

The cohort consisted of 1773 adults who had biopsy-confirmed NAFLD and at least 48 weeks of follow-up. The study population included 162 people who had completed a 72-week study of obeticholic acid or placebo as treatment for NASH. Participants were followed for a median of four years.

The study population was 64% female, 85% White and 12% Hispanic. Fifty-five per cent had NASH, 20% had borderline steatohepatitis and the remainder had fatty liver disease without NASH. Thirty per cent had F3 fibrosis or cirrhosis (F4 fibrosis). Almost all participants with F3 or F4 fibrosis had NASH (97% and 93%, respectively).

Co-morbidities were common in study participants; 61% had hypertension and 42% had diabetes. Six per cent had chronic kidney disease and 6% had experienced at least one cardiac event. These underlying conditions were more common at baseline in people with cirrhosis compared to those with F0 to F2 fibrosis.

Mortality was associated with fibrosis stage at baseline. In people with F0 to F2 fibrosis at baseline, the death rate was 0.32 deaths per 100 person-years of follow-up, compared to 1.76 deaths per 100 person-years in people with F4 fibrosis (cirrhosis). People with F4 fibrosis were almost four times more likely to die during follow-up compared to people with F0-F2 fibrosis (hazard ratio 3.9, 95% confidence interval 1.8-8.4).

Liver-related mortality and liver decompensation were also more frequent in people with F4 fibrosis, who were over 12 times more likely to die of a liver-related cause during follow-up compared to people with F0-F2 fibrosis (HR 12.7, 95% CI 1.8-88.6). A total of 37 patients had a new decompensation event during follow-up and the incidence of decompensation increased with fibrosis stage, from 0.05 per 100 person-years in people with F0-F2 fibrosis to 2.69 per 100 person-years in people with F4 fibrosis.

In a previous study, the NASH Clinical Research Network reported that 14% of participants progressed from F0-F2 fibrosis to F3 fibrosis and 2% progressed to F4 fibrosis during a median follow-up period of 4.5 years

The study investigators say that experimental agents for the treatment of NASH should be evaluated according to their efficacy in preventing progression to liver cirrhosis. Studies should also investigate whether treatments that result in the regression of liver fibrosis also lead to a reduction in liver decompensation in people with NASH.

But in short-term studies, NASH resolution or a 2-point reduction in the NAFLD activity score may be appropriate markers for clinical trials of NASH treatments.


Sanyal A et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. New England Journal of Medicine, 385: 1559-1569, 2021.