Quantitative assessment of liver fibrosis reveals a nonlinear association with fibrosis stage in nonalcoholic fatty liver disease

Abstract

Accurate staging of liver fibrosis is crucial to guide therapeutic decisions for patients with nonalcoholic fatty liver disease (NAFLD). Digital image analysis has emerged as a promising tool for quantitative assessment of fibrosis in chronic liver diseases. We sought to determine the relationship of histologic fibrosis stage with fiber amounts quantified in liver biopsy specimens for the better understanding of NAFLD progression. We measured area ratios of collagen and elastin fibers in Elastica van Gieson‐stained biopsy tissues from 289 patients with NAFLD from four hospitals using an automated computational method and examined their correlations with Brunt's fibrosis stage. As a secondary analysis, we performed multivariable logistic regression analysis to assess the associations of the combined area ratios of collagen and elastin with noninvasive fibrosis markers. The combined fiber area ratios correlated strongly with Brunt's stage (Spearman correlation coefficient, 0.78; P < 0.0001), but this relationship was nonlinear (P = 0.007) with striking differences between stage 4 (median area ratios, 12.3%) and stages 0‐3 (2.1%, 2.8%, 4.3%, and 4.8%, respectively). Elastin accumulation was common in areas of thick bridging fibrosis and thickened venous walls but not in areas of perisinusoidal fibrosis. The highest tertile of the combined fiber area ratios was associated with the fibrosis‐4 index and serum type IV collagen 7s domain (7s collagen) levels, whereas the upper two tertiles of the fiber amounts significantly associated with body mass index, aspartate aminotransferase, and 7s collagen in the multivariable analysis. Conclusion: Quantitative fibrosis assessment reveals a nonlinear relationship between fibrosis stage and fiber amount, with a marked difference between stage 4 and stage 3 and much smaller differences among stages 0‐3, suggesting a heterogeneity in disease severity within NAFLD‐related cirrhosis. (Hepatology Communications 2018;2:58–68)

Collagen proportionate area is an independent predictor of long‐term outcome in patients with non‐alcoholic fatty liver disease

“…In contrast, development of fibrosis in viral hepatitis is initially centred around the portal tract with subsequent rapid expansion towards the centrilobular vein . Existing studies on CPA measurement in NAFLD did not test higher magnifications and importantly did not validate CPA against clinical outcomes . We therefore tested different magnifications for digital analysis and CPA measurement in order to accurately quantify the presence of fine pericellular fibrosis that could be missed at a standard magnification.…”

Precision pathology analysis of the development and progression of hepatocellular carcinoma: Implication for precision diagnosis of hepatocellular carcinoma

“…The application of computer‐assisted quantitative analysis revealed that the pattern of liver fibrosis progression in NAFLD was different from that of chronic HCV infection: a striking difference was observed in fiber accumulation between Brunt's fibrosis stages F3 and F4 in NAFLD, in contrast to the somewhat linear association observed in chronic HCV infection . Moreover, the ranges of collagen and elastin levels in F4 stage NAFLD were larger than for stages F1–3 . Classical pathological staging systems have no stage beyond F4; however, it appears that fibrosis progresses and parenchymal remodeling continues even within the final fibrotic stage F4 .…”

“…20 Furthermore, advanced fibrosis is associated with an increased risk of mortality in NAFLD. 22 The application of computer-assisted quantitative analysis revealed that the pattern of liver fibrosis progression in NAFLD was different from that of chronic HCV infection: a striking difference was observed in fiber accumulation between Brunt's fibrosis stages F3 and F4 in NAFLD, 23 in contrast to the somewhat linear association observed in chronic HCV infection. 24 Moreover, the ranges of collagen and elastin levels in F4 stage NAFLD were larger than for stages F1-3.…”

Preliminary Evaluation of the Utility of Deep Generative Histopathology Image Translation at a Mid-Sized NCI Cancer Center

“…Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and resultant inflammation causing progressive liver injury and fibrosis in patients where no alcoholic, genetic, metabolic, or medication-based causes for hepatitis have been identified (Masugi et al, 2017). Progressive NASH can lead to cirrhosis which causes a markedly increased risk of hepatocellular carcinoma (HCC) and can require transplantation in end stage disease (causing a major human and financial impact on the healthcare system).…”

“…Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and chronic inflammation causing progressive liver injury and fibrosis in patients where no alcoholic, genetic, metabolic, or medication-based causes for hepatitis have been identified (Masugi et al, 2017). Progressive NASH can lead to cirrhosis with morbidities including ascites, sepsis, coagulopathies, and nutritional deficiencies, and a markedly increased risk of hepatocellular carcinoma (HCC).…”