The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease

Abstract

Although nonalcoholic fatty liver disease (NAFLD) is conventionally assessed histologically for lobular features of inflammation, development of portal fibrosis appears to be associated with disease progression. We investigated the composition of the portal inflammatory infiltrate and its relationship to the ductular reaction (DR), a second portal phenomenon implicated in fibrogenesis. The portal inflammatory infiltrate may contribute directly to fibrogenesis as well as influence the fate of the DR hepatic progenitor cells (HPCs), regulating the balance between liver repair and fibrosis. The presence of portal inflammation in NAFLD was strongly correlated with disease severity (fibrosis stage) and the DR. The portal infiltrate was characterized by immunostaining NAFLD liver biopsy sections (n = 33) for broad leukocyte subset markers (CD68, CD3, CD8, CD4, CD20, and neutrophil elastase) and selected inflammatory markers (matrix metalloproteinase 9 and interleukin [IL]‐17). Cells expressing all markers examined were identified throughout the liver lobules and in portal tracts, although portal tracts were more densely populated (P < 0.01), and dominated by CD68+ macrophages and CD8+ lymphocytes, at all stages of disease. An increase in portal macrophages in NAFLD patients with steatosis alone (P < 0.01) was the earliest change detected, even before elevated expression of the proinflammatory cytokines, IL1B and TNF, in patients with early NASH (P < 0.05). Portal and periductal accumulation of all other cell types examined occurred in progressed NASH (all P < 0.05). Conclusion: Knowledge of the complex cellular composition of the portal inflammatory infiltrate and HPC/DR niche in NAFLD will shape future functional studies to elucidate the contribution of portal inflammation to HPC differentiation and NAFLD pathogenesis. (Hepatology 2014;59:1393‐1405)

Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver

“…The inflammatory process and underlying immunological mechanisms in NASH are not well understood. Cells expressing several T cell markers were recently identified by immunostaining in NAFLD liver biopsy sections (20). In this study, we analyzed the peripheral and hepatic composition of CD4 + T cells in patients with NASH in comparison with NAFL in unprecedented detail, with ex vivo analysis of immune cells in the liver and peripheral blood.…”

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

“…Indeed, inflammatory infiltration occurs in SS and NASH together with increased hepatic expression of inflammatory cytokines (Gadd et al, 2014). Inflammatory cytokines, acting through nuclear factor k-light-chain-enhancer of activated B cells, causes transrepression of the pregnane X receptor, a central transcription factor regulating CYP3A4 expression (Gu et al, 2006;Zhou et al, 2006).…”

A Fibroblast Growth Factor 21–Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease

“…3). Portal inflammation occurs in NAFLD livers in the early stages of simple steatosis and as disease progresses to NASH, resulting in increased levels of hepatic cytokines (Gadd et al, 2014). The degree of hepatic inflammation is likely to correspond to lower CYP3A4 expression given that inflammatory cytokines suppress drug-metabolizing enzyme gene expression (Abdel-Razzak et al, 1993) through mutual repression of PXR and nuclear factor-kB transcriptional activities (Zhou et al, 2006).…”