Table 1.
Clinical studies that have assessed the role of general inflammatory biomarkers and cytokines to predict outcomes in NAFLD.
| Reference | Biomarker | Number of patients | Results |
|---|---|---|---|
| Park et al. (16) | CRP | 120 non-obese patients with NAFLD and 240 matched controls | Multivariate analysis showed that CRP (OR = 1.37; 95% CI 1.06–1.77 per 1 SD increase) and HOMA-IR [OR = 2.28; 95% CI: 1.67–3.11, per 1 SD (0.63)] were independent risk factors for NAFLD in non-obese patients |
| Yoneda et al. (19) | Hs-CRP and CRP mRNA | 100 patients with NAFLD (29 with steatosis and 71 with NASH) | Patients with NASH had significantly elevated serum hs-CRP (P < 0.0048) and increased intrahepatic expression of the CRP mRNA (P = 0.0228) than those with simple steatosis. In addition, patients with advanced fibrosis stages (F3–4) had a significantly higher serum hs-CRP than those with mild (F1–2) (P < 0.0384), even after adjustment for confounders |
| Oruc et al. (54) | CRP | 50 NAFLD cases and 50 healthy controls | Serum CRP levels were significantly higher in simple steatosis and NASH groups compared to healthy controls (mean: 7.5 and 5.2 vs. 2.9 mg/dl, respectively, P < 0.01) |
| Riquelme et al. (18) | Hs-CRP | 832 Hispanic subjects who underwent abdominal ultrasound | The prevalence of NAFLD was 23%. A high hs-CRP (>0.86 mg/L) was associated with NAFLD in multivariate analysis (OR 2.9; 95% CI 1.6–5.2); as was a high body mass index, abnormal aspartate aminotransferase, and insulin resistance |
| Zimmermann et al. (44) | Hs-CRP | 627 obese adults | A positive association between degree of steatosis and hs-CRP was observed (P < 0.05), and this effect remained significant after adjusting for BMI, lobular inflammation, hepatocyte ballooning, and fibrosis |
| Wang et al. (55) | Hs-CRP | 8,618 initially NAFLD-free Chinese subjects who underwent annual health screen | The hs-CRP level was independently associated with NAFLD. The incidence ratio of NAFLD increased significantly with increasing hs-CRP quartiles either in man (21.1, 18.6, 24.8, and 31.1% for the first, second, third, and fourth quartiles, respectively), and in females (6.2, 6, 11.4, and 19.5% for the first, second, third, and fourth quartiles, respectively). The association was stronger in females than in males |
| Cayón et al. (49) | TGF-β1 and leptin systems | 90 subjects with NAFLD (55 with NASH and 35 with simple steatosis) | There was a marked increase in intrahepatic gene expression of TGF-β1 (P = 0.0002), leptin receptor mRNA (P = 0.0016), and its protein (P < 0.05) in patients with NASH. A strong correlation was shown between leptin receptor gene expression and TGF-β1 gene expression (P = 0.023) |
| Wei et al. (50) | TGF-β3 | 1,322 healthy subjects without other risk factors, followed during 4 years | After 4 years of follow-up, the cumulative incidence of NAFLD was 25.3% (334/1,322). Those who developed NAFLD had higher serum TGF-β3 levels than those who did not (mean 554 vs. 285 pg/ml; P < 0.002); and the incidence increased significantly with increasing TGF-β3 tertiles (6.3, 38.0, and 55.7%, for the first, second, and third tertiles, respectively; P < 0.05) |
| Wieckowska et al. (46) | IL-6 and IL-6 mRNA | 50 patients with suspected NAFLD | IL-6 mRNA expression was markedly increased in the livers of patients with NASH than in those with simple steatosis (P < 0.005) or normal biopsies (P < 0.010). There was a positive correlation between hepatocyte IL-6 mRNA expression and degree of inflammation, stage of fibrosis, plasma IL-6 levels, and degree of systemic insulin resistance |
| Bahcecioglu et al. (56) | TNF-α and IL-8 | 42 patients (28 with NASH and 14 with cirrhosis) and 15 healthy controls | Serum TNF-α levels were significantly higher in patients with NASH and cirrhosis than in healthy controls (P < 0.05). Serum IL-8 levels in patients with NASH (P < 0.001) and cirrhosis (P < 0.05) were significantly higher than in the healthy control group |
| Coulon et al. (43) | TNF-α, IL-6, and TNF-α mRNA | 92 subjects (30 obese with steatosis, 32 with NASH, and 30 healthy controls) | In comparison with controls, serum IL-6 was significantly high both in simple steatosis (mean 2.863 vs. 1.224 pg/ml; P < 0.001) and NASH patients (mean 3.136 vs. 1.224 pg/ml; P < 0.001), whereas serum TNF-α elevation was only significant in NASH group (mean 1.803 vs. 1.405 pg/ml; P = 0.026). Patients with NASH had a significantly higher expression of TNF-α mRNA in liver tissue than those with simple steatosis |
| Seo et al. (57) | TNF-α | 363 apparently healthy subjects | At 4 years of follow-up, the cumulative incidence of NAFLD was 29.2% (106/363). Those who developed NAFLD had higher serum TNF-α levels than those who did not (mean 3.65 vs. 3.15 pg/ml; P < 0.01). The incidence of NAFLD increased significantly with increasing TNF-α tertiles (22.6, 35.8, and 41.5%, for the first, second, and third tertiles, respectively; P < 0.05). The risk of developing NAFLD was significantly higher in the highest tertile of TNF-α than in the lowest (OR, 2.20; P < 0.05) |
| Paredes-Turrubiarte et al. (58) | TNF-α and IL-10 | 102 morbidly obese | Patients with NAFLD showed increased TNF-α than those with morbidly obese subjects but without NAFLD (mean 37.41 vs.31.41 pg/ml, P < 0.046). Serum levels of IL-10, in contrast, were decreased in NAFLD (mean 61.05 vs. 76.40 pg/ml, P < 0.002), which suggests an imbalance between the pro-inflammatory and anti-inflammatory cytokines |
| Tang et al. (29) | IL-17, IL-21, and IL-23 | 58 human liver specimens (14 with NASH and 40 controlsb)a | There was a significant increase of IL-17(+) cells infiltrating the liver of NASH patient and increased gene expression of Th17 cell-related cytokines (IL-17, IL-21, and IL-23). Hepatic Th17 cells and IL-17 were associated with steatosis and pro-inflammatory response in NAFLD and facilitated the transition from simple steatosis to steatohepatitis |
| Okumura et al. (59) | LECT2 | 231 Japanese adult tested for LECT2 | Serum LECT2 was significantly high in patients with fatty liver than in those without (mean 48.7 vs. 140.5 ng/ml; P < 0.001) |
HOMA-IR, homeostasis model assessment-insulin resistance; IL-10, interleukin-10; IL-17, interleukin-17; IL-21, interleukin-21; IL-23, interleukin-23; IL-6, interleukin-6; mRNA, messenger RNA; NASH, non-alcoholic steatohepatitis; LECT2, leukocyte cell-derived chemotaxin 2; TNF-α, tumor necrosis factor-alpha.
aThe study included animal experiments.
bControl specimens obtained from the liver tissues besides resected hemangiomas.