Serum Interleukin‐8, Osteopontin, and Monocyte Chemoattractant Protein 1 Are Associated With Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

Abstract

The severity of hepatic fibrosis is the primary predictor of liver‐related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD‐associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy‐proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0‐1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3‐4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin‐8 (IL‐8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, hepatocyte ballooning, age, sex, body mass index, diabetes mellitus, hypertension, and metabolic syndrome status, IL‐8 remained strongly associated with fibrosis (P = 0.001). Furthermore, IL‐8 was also a strong predictor of increased fibrotic liver injury compared to established markers of hepatic fibrosis. Hepatic gene expression from 72 patients with NAFLD (n = 40 mild fibrosis; n = 32 advanced fibrosis) from the Duke University Health System NAFLD Clinical Database and Biorepository revealed IL‐8, MCP1, and OPN gene expression to be increased and differentially expressed in patients with advanced hepatic fibrosis. Thus, serum IL‐8, MCP1, and OPN may reflect up‐regulated gene expression during liver fibrosis in NAFLD. Conclusion: Serum IL‐8, MCP1, and OPN may serve as a test for advanced hepatic fibrosis in NAFLD and thus reveal novel targets for antifibrotic therapies. The increased serum IL‐8, MCP1, and OPN that correspond with associated hepatic gene expression lend strength to such analytes as ideal surrogate serum biomarkers for severity of hepatic fibrosis.

Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease

“…Human NASH and fibrosis are related to increased OPN levels (Glass et al., 2018), and the current results show that liver OPN prevents age‐related early accumulation of lipids, senescence, and ER stress. We next evaluated whether OPN was also required to prevent fibrosis in the aged mice.…”

Bile‐Derived Organoids From Patients With Primary Sclerosing Cholangitis Recapitulate Their Inflammatory Immune Profile

“…We did note, however, that the PSC patient with the highest level of biliary IL‐8 also had higher gene expression for IL‐8 and was the one patient in our study with cirrhosis. A recent publication found elevated serum IL‐8 in patients with more advanced fibrosis due to nonalcoholic fatty liver disease …”

“…This is similar to a recent report where high serum levels of IL-8 correlated with advanced fibrosis in nonalcoholic fatty liver disease. (27) In addition, BDOs are a potential approach to the study of specific features of PSC. Most importantly, organoids from patients with PSC expressed markers of an immune phenotype consisting of CCL20, HLA-DMA, and CD74 compared to non-PSC patients.…”

“…A recent publication found elevated serum IL-8 in patients with more advanced fibrosis due to nonalcoholic fatty liver disease. (27) We then tested whether BDOs could be stimulated to secrete chemokines/cytokines. Based upon reports that IL-17 can stimulate bile epithelial cells to secrete CCL20, (26) we incubated the BDOs with IL-17A (50 ng/mL for 48 hours) and measured gene expression and secretion into the culture supernatant.…”

Proteomic screening of plasma identifies potential noninvasive biomarkers associated with significant/advanced fibrosis in patients with nonalcoholic fatty liver disease

“…methods [2][3][4][5][6][7][8][9][10][11][12], including imaging modalities [13][14][15][16][17], biomarkers [18][19][20][21][22][23][24][25][26], and artificial intelligence algorithms [27][28][29][30][31][32].…”