Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease

Abstract

Importance: The histologic evolution of the full spectrum of nonalcoholic fatty liver disease (NAFLD) and factors associated with progression or regression remain to be definitively established.

Objective: To evaluate the histologic evolution of NAFLD and the factors associated with changes in disease severity over time.

Design, setting, and participants: A prospective cohort substudy from the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database study, a noninterventional registry, was performed at 8 university medical research centers. Masked assessment of liver histologic specimens was performed, using a prespecified protocol to score individual biopsies. Participants included 446 adults with NAFLD enrolled in the NASH CRN Database studies between October 27, 2004, and September 13, 2013, who underwent 2 liver biopsies 1 or more year apart. Data analysis was performed from October 2016 to October 2018.

Main outcomes and measures: Progression and regression of fibrosis stage, using clinical, laboratory, and histologic findings, including the NAFLD activity score (NAS) (sum of scores for steatosis, lobular inflammation, and ballooning; range, 0-8, with 8 indicating more severe disease).

Results: A total of 446 adults (mean [SD] age, 47 [11] years; 294 [65.9%] women) with NAFLD (NAFL, 86 [19.3%]), borderline NASH (84 [18.8%]), and definite NASH (276 [61.9%]) were studied. Over a mean (SD) interval of 4.9 (2.8) years between biopsies, NAFL resolved in 11 patients (12.8%) and progressed to steatohepatitis in 36 patients (41.9%). Steatohepatitis resolved in 24 (28.6%) of the patients with borderline NASH and 61 (22.1%) of those with definite NASH. Fibrosis progression or regression by at least 1 stage occurred in 132 (30%) and 151 [34%] participants, respectively. Metabolic syndrome (20 [95%] vs 108 [72%]; P = .03), baseline NAS (mean [SD], 5.0 [1.4] vs 4.3 [1.6]; P = .005), and smaller reduction in NAS (-0.2 [2] vs -0.9 [2]; P < .001) were associated with progression to advanced (stage 3-4) fibrosis vs those without progression to stage 3 to 4 fibrosis. Fibrosis regression was associated with lower baseline insulin level (20 vs 33 μU/mL; P = .02) and decrease in all NAS components (steatosis grade -0.8 [0.1] vs -0.3 [0.9]; P < .001; lobular inflammation -0.5 [0.8] vs -0.2 [0.9]; P < .001; ballooning -0.7 [1.1] vs -0.1 [0.9]; P < .001). Only baseline aspartate aminotransferase (AST) levels were associated with fibrosis regression vs no change and progression vs no change on multivariable regression: baseline AST (regression: conditional odds ratio [cOR], 0.6 per 10 U/L AST; 95% CI, 0.4-0.7; P < .001; progression: cOR, 1.3; 95% CI, 1.1-1.5; P = .002). Changes in the AST level, alanine aminotransferase (ALT) level, and NAS were also associated with fibrosis regression and progression (ΔAST level: regression, cOR, 0.9; 95% CI, 0.6-1.2; P = .47; progression, cOR, 1.3; 95% CI, 1.0-1.6; P = .02; ΔALT level: regression, cOR, 0.7 per 10 U/L AST; 95% CI, 0.5-0.9; P = .002; progression, cOR, 1.0 per 10 U/L AST; 95% CI, 0.9-1.2; P = .93; ΔNAS: regression, cOR, 0.7; 95% CI, 0.6-0.9; P = .001; progression, cOR, 1.3; 95% CI, 1.1-1.5; P = .01).

Conclusions and relevance: Improvement or worsening of disease activity may be associated with fibrosis regression or progression, respectively, in NAFLD.

Figure 1.. Flow Diagram Showing Participants Evaluated and Included in the Study

FLINT indicates the Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial; PIVENS, Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis Trial; and NAFLD, nonalcoholic fatty liver disease. ^aThe total number of biopsies was 1059.

Figure 2.. Examples of Progression and Regression of Nonalcoholic Fatty Liver Disease (NAFLD)

Changes in diagnosis and fibrosis from first biopsy to last showing numbers of patients with changes of diagnosis (A) or fibrosis stage (B). Green boxes indicate improved diagnosis or regression of fibrosis; red boxes indicate worsening diagnosis or progression of fibrosis. White boxes indicate either no change in diagnosis or fibrosis stage or, in the case of off-diagonal boxes (B), a change in fibrosis that cannot be clearly defined as progression or regression. SH indicates steatohepatitis.

Figure 3.. Histologic Evolution of Nonalcoholic Fatty Liver Disease (NAFLD)

A-C, The proportion of patients with fibrosis stage 0, 1a, 1b, 1c, 2, 3, or 4 at first biopsy and last biopsy is shown in patients whose diagnosis improved, did not change, and worsened. A, For those with improvement in diagnosis, fibrosis stage is shown for those with diagnosis change from nonalcoholic steatohepatitis (NASH) to nonalcoholic fatty liver (NAFL) (n = 61), borderline to NAFL (n = 24), and NASH to borderline (n = 56). B, For patients with no change in diagnosis, fibrosis stage is shown for NAFL (n = 50) borderline (n = 21), and NASH (n = 159). C, For patients with worsening of diagnosis, fibrosis stage is shown for those with diagnosis change from NAFL to NASH (n = 18), borderline to NASH (n = 39), and NAFL to borderline (n = 18). D, The change in fibrosis stage from the first biopsy to the second is shown as a function of change in the NAFLD activity score (NAS). A reduction in the NAS was associated with a decrease in fibrosis stage, whereas an increase in the NAS was associated with an increase in fibrosis stage. Specifically, a 2-point or greater decrease in NAS was associated with fibrosis regression. One participant with a change in NAS of −7 and 1 participant with a change in NAS of +5 were removed from the figure. Spearman correlation coefficient, 0.38; slope, +0.67; SE, 0.08; P < .001. Error bars indicate 95% CIs.